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ENDOCRINE REGULATIONS, Vol. 46, 167–186, 2012 Molecular and hereditary mechanisms of sensorineural hearing loss with
focus on selected endocrinopathies
1*Masindova I, 1,2*Varga L, 1,3Stanik J, 1Valentinova L, 2Profant M, 1Klimes I, 1Gasperikova D 1Laboratory of Diabetes and Metabolic Disorders & DIABGENE, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia; 21st ORL Clinic, Faculty of Medicine and University Hospital, Comenius University, Bratislava, Slovakia; 31st Department of Pediatrics, Faculty of Medicine, Comenius University, Bratislava, Slovakia * Masindova I and Varga L contributed equal y to this work. Abstract. Hearing loss is one of the most widespread sensory disorders. The incidence of deafness
in general population is 1:1000 newborns. About one half of the congenital sensorineural hearing loss (SNHL) cases is inherited. Recessive mutations in the gap junction beta 2 (GJB2) gene are the most common genetic causes of the nonsyndromic SNHL. The GJB2 encodes a protein connexin 26 which forms a subunit of gap junction essential for the correct function of the inner ear. The syndromic SNHL is associated with a wide range of other symptoms, which encompass also dysfunctions of endocrine organs. The Pendred syndrome associated with the hearing impairment is characterized by a prelingual, bilateral sever to profound SNHL, goiter, and iodine organification defect. It is an autosomal recessive disorder, which develops due to mutations in pendrin, an anion channel encoded by SLC26A4 gene. Another important type of syndromic hearing loss is the Maternal y Inherited Diabetes and Deafness syndrome, which is caused by several mitochondrial DNA mutations. These mutations are clinical y manifested by a hearing impairment with development of the diabetes in the adult age. Hearing impairment occurs during puberty when sensation of high frequency tones is affected following with further progress to profound bilateral sensorineural hearing impairment in the whole frequency range. This review deals with the molecular mechanisms of common genetic causes of the hereditary SNHL along with the selected endocrinopathies emphasizing that the DNA analyses along with the functional studies significantly contribute to the early SNHL diagnosis fol- lowed by personalized therapy and genetic counseling.
Keywords: hearing impairment, inner ear, connexin, Pendred syndrome, diabetes
sensorineural hearing loss
is 1:1000 in newborns (Morton 1991); however, the etiology of the hearing disorders is extremely diverse. Hearing loss is one of the most common sensory dis-
Approximately half of the congenital sensorineural hear- orders. Based on the World Health Organization's data, ing loss (SNHL) is caused by genetic abnormalities, 25% over 278 million people suffer from the hearing loss by environmental factors, and the remaining 25% has (WHO 2010). The incidence of profound hearing loss unknown origin (Morton 1991; Schrijver 2004).
Corresponding author: Daniela Gasperikova, PhD., Laboratory of Diabetes and Metabolic Disorders & DIABGENE, Institute of
Experimental Endocrinology, Slovak Academy of Sciences, Vlarska 3, 833 06 Bratislava, Slovakia; phone: + 421-2-5477-2800; fax: SENSORINEURAL HEARING LOSS AND ENDOCRINOPATHIES The hereditary hearing loss is usual y manifested by of potassium ions, which are necessary for its proper a bilateral damage of the inner ear or auditory pathway function (Wangemann 2006).
– nervus vestibulocochlearis, which is referred as bilateral The nonsyndromic or syndromic SNHL connected SNHL. It can be present in a nonsyndromic form (70%), with the goiter (Pendred syndrome) appears on the basis as a single disorder, or syndromic form (30%) associated of the SLC26A4 gene mutations (Everett et al. 1997). This with dysfunction of other organs (Van Camp et al. 1997; gene encodes a protein transporter pendrin, which is Acmg 2002). The hereditary SNHL is characterized by expressed in several cochlear cell types, follicular cel s autosomal recessive (80%), autosomal dominant (15 in thyroid gland, and kidneys. Mutations of the mito- to 20%), x-linked (1%) or mitochondrial inheritance chondrial DNA contribute significantly to the hearing (1 to 5%) (Pandya et al. 1999; Schrijver 2004). For the impairment etiology and can induce syndromic as well normal hearing, correct function of about 300 genes is as nonsyndromic hearing loss. Considering that the required (Friedman and Griffith 2003). Concerning the mitochondrial dysfunctions affect also the inner ear etiology of hearing impairment, the GJB2 is the most (as the organ with high metabolic activity), the SNHL frequently involved gene encoding the protein connexin is a frequent clinical symptom of the mitochondrial (Cx) 26. The GJB2 gene mutations are the most common diseases (Fischel-Ghodsian 2003).
reasons of the nonsyndromic deafness development in the Caucasoid population (Kelsell et al. 1997; Estivill snHL caused by defect of connexins
et al. 1998a). The second most frequent reason of the nonsyndromic SNHL occurrence in some countries is Connexins (Cxs) represent protein subunits of an
a large deletion in the GJB6 gene encoding Cx30 (Del intercel ular gap junction. To date, 21 Cx genes have Castillo et al. 2003). The connexins forming intercel u- been identified in the human genome (Rackauskas lar connections (gap junction) in the inner ear cochlea et al. 2010). The genes that encode individual Cxs are play an important role in the transport and recycling named according to sequential homology arranged into Fig. 1. a) structure of connexin consisting of four transmembrane domains (m), two extracellular loops (el) and one intracel-
lular loop (el). The amino-terminus and carboxyl-terminus are localized in cytoplasm. b) Dotted circles indicate a gap j
channel, connexon and connexin. Gap junction channel types revised according to Wagner (2008).
SENSORINEURAL HEARING LOSS AND ENDOCRINOPATHIES 5 groups (α, β, γ, δ and ε) (Pfenniger et al. 2011). Proteins snHL induced by the defect of Cx26 is the most
are classified according to their size in kDa. The primary frequent hereditary cause of this disease (Hilgert et al. structure and topology of Cxs within the protein sub- 2009a). Other Cxs, such as Cx30, Cx31, and Cx43, are family is common. They consist of four alpha-helical only rarely involved in the etiology of the hearing disor- transmembrane domains (m1-m4) connected by two ders (Liu et al. 2001; Hong et al. 2010). The Cx26 protein is extracel ular (el1, el2) and one intracel ular loop (cl1) encoded by the GJB2 gene located on the long arm of the (Fig. 1a). The transmembrane domains and extracel- chromosome 13 (13q11-q12). The GJB2 gene is composed lular loops are highly conserved. The cytoplasmic loop of 2 exons, one which encodes 5' untranslated region (5' and protein carboxyl terminus are unique for each Cx, UTR) and the another which encodes the complete open differing in the length and composition of the amino reading frame (ORF) and 3' untranslated region (3' UTR) acids (Saez et al. 2003; Herve et al. 2004). Six Cx units (Saez et al. 2003). The protein is composed of 226 amino compose one hemichannel called connexon. The con- acids, with a molecular weight of 26 kD.
nexons of two adjacent cel s dock and constitute a gap Currently more than 90 pathogenic mutations in
junction (Bruzzone et al. 1996). Depending on the com- the GJB2 gene have been identified with a significant
position of the channels, the Cxs can be homomeric, if contribution of the frameshift and nonsense mutations they consist of one Cx isoform, or heteromeric, if they (http://davinci.crg.es/deafness/). The frequency of the consist of two different Cx isoforms. The gap junction individual mutations varies within the ethnic groups. channels may also be divided into homotypic or het- In the Caucasoid population, the most frequent muta- erotypic form, depending on the presence of the Cx tion is c.35delG a recessive deletion of one of the six types. The homotypic gap junctions are made by one guanines at the codon position 30 – 35 (Denoyelle Cx isoform, the heterotypic by two different connexons et al. 1997; Zelante et al. 1997). This deletion leads to (Fig. 1b) (Bruzzone et al. 1996).
the shifted reading frame, creation of stop codon, and The gap junctions allow direct passage of ions, smal premature termination of the connexin 26 synthesis molecules and other metabolites between cel s including (Denoyel e et al. 1997). In Ashkenazi Jews, the most molecules functioning as second messengers - cAMP, frequent mutation is a recessive deletion of the thymine cGMP, IP ATP - or other metabolites up to 1 kDa in at position 167 (c.167delT) which also causes frameshift size (Saez et al. 2003; Martinez et al. 2009). Voltage- and premature stop codon (Zelante et al. 1997). In Asian dependent gating of hemichannels composed of Cx26 countries, Japan, China, and Korea, the frameshift is affected by the presence of a helical structure in the mutation c.235delC dominates (Fuse et al. 1999; Park amino-terminus (N), which is embedded into the lumen et al. 2000; Liu et al. 2002). Concerning the Indian and of the channel (Maeda and Tsukihara 2011). Each helical Pakistani populations, the recessive nonsense mutation structure of N-terminus during voltage equilibrium state of c.71G>A prevails (Kelsell et al. 1997) which was also interacts with the transmembrane domain 1 of its own found with high frequency in Roma populations in Cx molecule. Six helical structures of the hemichannel several countries, Slovak Republic, Czech Republic, and are directed into a pore creating the narrowest part of the Spain (Minarik et al. 2003; Seeman et al. 2004; Alvarez channel entrance cal ed pore funnel. When membrane et al. 2005). The pathogenic GJB2 mutations found in potential between adjacent cel s changes, the N-terminus Slovakia, Czech Republic, Austria, and Hungary are structures are released from the transmembrane domains listed in Table 1.
into the pore. They gather at the end of the pore and form The effect of mutations on the protein function is
structures, so called plugs that close the channel (Purnick not completely known due to complexity of the gap junc- et al. 2000; Maeda and Tsukihara 2011).
tion channels structure (Snoeckx et al. 2005). However, Several isoforms of the Cxs are expressed in the in- based on the different gap junction defects, mutations ner ear cochlea. These particularly include the Cx26 in the GJB2 can be divided into several groups (Hoang and Cx30 and to a lesser extent the Cx31, Cx32, Cx43, Dinh et al. 2009).
and Cx45 (Zelante et al. 1997; xia et al. 1998; Grifa et The first group includes mutations preventing the al. 1999; Liu et al. 2001). The Cxs play an important docking of the gap junction channel. These mutations role in the recirculation of K+ ions. The defects of Cxs involve the inhibition of various processes: 1) oligom- in the inner ear result in disruption of K+ recirculation erisation of the Cxs into hemichannels, 2) transport and leading to hearing loss (Martinez et al. 2009) (for details incorporation of hemichannels in the membrane or 3) see Fig. 2).
connexons connection between the cel s and docking SENSORINEURAL HEARING LOSS AND ENDOCRINOPATHIES Fig. 2. Upper-left figure shows the cross section of the ear and its individual parts, with highlighted location of inner ear cochlea.
Flow directions of potassium ions are visible in the cross section of the cochlea itself. Cochlea is composed of three parts: scala
vestibuli, scala tympani, filled with perilymph. Between these two parts there is scala media with a fluid, the endolymph. Potassium
cations pass from endolymph to hair cells and then are transported to supporting cells organ of Corti. Among the supporting cells,
K+ ions pass through gap junction channels formed by connexins 26 and 30 as far as to the cells of spiral ligament and stria vascula-
ris. Potassium ions are actively transported from stria vascularis cells back to endolymph. Potassium cations from supporting cells
are also transported to perilymph, from which they pass to cells of spiral ligament and stria vascularis and to endolymph. Revised
according to Mammano et al. (2007) and .
of the gap junction (Thonnissen et al. 2002; de Zwart- The third group includes mutations specifical y dam- Storm et al. 2008; Maeda and Tsukihara 2011). For aging the biochemical coupling of the gap junction. For instance, these include c.35delG (Zelante et al. 1997), example, the recessive substitution c.250G>C selectively oligomerisation-deficient mutant c.551G>C (Thon- decreases the membrane permeability for the inositol nissen et al. 2002) or dominant substitution c.548C>T trisphosphate (IP ) through gap junction (Beltramel o et which prevents hemichannels from joining to form gap al. 2005). However, the importance of IP for the correct junction (de Zwart-Storm et al. 2008).
gap junction function in cochlea is not ful y understood The second group consists of mutations resulting yet (Hoang Dinh et al. 2009).
in the creation of the gap junction channels with no The fourth group contains gain of function muta- function. The connexons are incorporated into the tions with abnormal opening of the hemichannels and membrane forming gap junction plaques associated increased gap junction activity. The examples include with the loss of the hemichannel activity (Hoang Dinh dominant mutations, c.134G>A (Gerido et al. 2007), et al. 2009). For example, the dominant point substitu- c.34G>C or c.148G>A, leading to an increased channel tion c.223C>T shows a complete loss of channel voltage permeability, and thus resulting in the cell death (Lee sensitivity (Chen et al. 2005; Lee et al. 2009).
et al. 2009).
SENSORINEURAL HEARING LOSS AND ENDOCRINOPATHIES List of pathogenic substitutions and deletions in the GJB2 gene identified in slovakia (sK) (Minarik et al. 2012), Czech Repub-
lic (CZ) (seeman et al. 2004), Austria (A) (Frei et al. 2002; 2004) and Hungary (H) (toth et al. 2004)
Nucleotide
Inheritance
position
position
Clinical condition
Hearing impairment Hearing impairment Hearing impairment p.Val52Leu not determined AN, Hearing impairment Deletions
Hearing impairment not determined Hearing impairment SNHL – sensorineural hearing loss, AN – auditory neuropathy, AR – autosomal recessive, AD – autosomal dominant Mutations in the Cx26 are manifested by nonsyn-
may also develop in compound heterozygous form of dromic or syndromic snHL. The nonsyndromic
the GJB2 mutation with the second mutation in GJB6 snHL is mainly caused by mutations with autosomal
(Cx30) or GJB3 (Cx31) (Liu et al. 2009; Rodriguez-Paris recessive manner of inheritance (Hilgert et al. 2009a). and Schrijver 2009). In the case of compound hetero- Almost half of the recessive mutations are frameshift zygote of two genes, the expression of these genes is or nonsense type (Pfenniger et al. 2011). They have no probably affected (Ortolano et al. 2008) which is not specific localization within the protein and can be found due to digenic inheritance as previously assumed (Lerer in al Cx26 domains (Martinez et al. 2009). Hearing et al. 2001). The level of hearing loss in the GJB2/GJB6 loss phenotype develops in recessive homozygotes or carriers may range from mild to profound (Rodriguez- compound heterozygotes GJB2 mutations. The SNHL Paris et al. 2011).
SENSORINEURAL HEARING LOSS AND ENDOCRINOPATHIES The syndromic snHL is caused by autosomal
countries. The loss of a possible cis-regulatory element dominant mutations, where hearing loss is manifested located upstream of the GJB6 gene was assumed as by a postlingual hearing loss phenotype (Hilgert et al. a potential mechanism for the developing hearing loss 2009a). Mutations are mostly found in the region of in carriers with GJB6 large deletions along with other the N-terminus and the first extracel ular protein loop GJB2/GJB6 mutations (Rodriguez-Paris and Schrijver (Martinez et al. 2009). Until now, one dominant muta- 2009). Extensive rearrangements cause a deletion of one tion has been described in the second extracel ular loop or more potential regulatory elements which may lead (de Zwart-Storm et al. 2008). The SNHL is manifested to a disruption of the GJB2 transcription (Feldmann et by hearing impairment associated with skin diseases, al. 2009; Rodriguez-Paris and Schrijver 2009; Wilch et for example the KID (Keratitis-Ichtyosis-Deafness) al. 2010; Rodriguez-Paris et al. 2011). The damage of the syndrome and palmoplantar keratoderma (Heathcote et Cx31 is rare in the nonsyndromic and syndromic SNHL al. 2000; Richard et al. 2002). It has been proposed that (Hilgert et al. 2009b). The Cx31 is encoded by the gap skin diseases related to the GJB2 mutations are caused junction beta 3 (GJB3) gene located on the short arm of by dominant-negative effect of the mutated Cx26, which the chromosome 1 (1p34). More than 10 GJB3 mutations affects other Cx isoforms, creating heteromeric gap junc- responsible for hearing loss are known. Syndromic SNHL tion channels and thus disrupting their normal func- may be accompanied by a peripheral neuropathy (Lopez- tion also in the skin. Theory of the dominant-negative Bigas et al. 2001), but mostly is linked to skin disease, effect is supported by several factors. All the syndromic Erythrokeratodermia variabilis (Kelsell et al. 2001). Two hearing disorders develop as a result of dominant muta- mutations in the GJA1 gene (located in chromosome 6), tions. The mutated Cx26 inhibits the co-expressed wild coding Cx43, were associated with SNHL and have been type Cx26, Cx30 or Cx43 in the exogenous expression reported in four Afro-American families (Liu et al. 2001). systems in a dominant-negative manner (Rouan et al. Afterwards, it has been proven that these mutations are 2001; de Zwart-Storm et al. 2008; Martinez et al. 2009). localized on the chromosome 5 in the pseudogene of The type of skin disease is closely related to the muta- Cx43 (rhoGJA1) (Paznekas et al. 2003). However, identifi- tion location. The KID syndrome is linked with muta- cation of three missense mutations in GJA1 and rhoGJA1, tions in the N-terminus and extracel ular loop 1. The as wel as their subsequent functional study suggest an Palmoplantar keratoderma is linked with mutations in association with the hearing loss (Hong et al. 2010).
the extracel ular loop 1 (Martinez et al. 2009).
The nonsyndromic and syndromic hearing loss
snHL and Pendred syndrome
may develop also due to damage of the Cx30, Cx31, and Cx43 (Hilgert et al. 2009b). The Cx30 is encoded by gap The SNHL is connected with more than 400 clinical junction beta 6 (GJB6) gene located on the short arm of syndromes (Hilgert et al. 2009b). One of the most fre- the chromosome 13, in close proximity to GJB2 (50 kb). quent is the Pendred syndrome, an autosomal recessive
The point mutations causing hearing impairment in disease characterized by bilateral SNHL, goiter, and GJB6 are relatively rare and only few of them have been positive perchlorate discharge test which reflects the identified (c.14C>T, c.63delG, c.119C>T, c.175G>C) iodine organification defect (Reardon and Trembath (Grifa et al. 1999; Gardner et al. 2006; Nemoto-Hasebe 1996). The estimated incidence is 7.5:100 000 in the et al. 2009; Wang et al. 2011). However, large deletions United Kingdom (Fraser 1965; Pryor et al. 2005) and of this gene, ranging from 131 kb to >920 kb, may occur accounts for approximately from 1 to 8% cases of the more frequently. Depending on their size and location, inborn deafness (Smith and Hone 2003).
these deletions affect not only GJB6 but also a number The Pendred syndrome develops due to mutations
of genes including the CRYL1, GJB2, GJA3, and ZMYM2 in the gene encoding the membrane protein - pendrin
(Feldmann et al. 2009; Wilch et al. 2010). Recessive dele- (Everett et al. 1997). Pendrin is an electroneutral anion tion of D13S1830 (309 kb) is the most prevalent. In some channel belonging to the family of SLC26 transporters countries, such as England, France or Spain, this deletion (Everett et al. 1997). It is composed of 780 amino acids was identified from 20 to 40% of the GJB2 mutation arranged into 11 or 12 transmembrane domains (Everett carriers (Del Castil o et al. 2003). Studies from Western et al. 1997; Royaux et al. 2000). In the C-terminus region Austria (Frei et al. 2004), Czech Republic (Seeman et al. is located a STAS domain (Sulfate Transporter Antagonist 2005), and Slovakia (Varga et al. 2011) have revealed only of Anti-Sigma Factor) which probably plays an important rare incidence of this mutation in the Central European role in the biosynthesis, function, and regulation of this SENSORINEURAL HEARING LOSS AND ENDOCRINOPATHIES transporter (Babu et al. 2010). Based on the sequence the inner ear, it plays a role in the maintaining of the pH homology, the pendrin is closely related to the family of value of the endolymph. The endolymph pH is slightly sulphate transporters; however, it does not provide the alkaline (Nakaya et al. 2007; Wangemann et al. 2007) transport of sulphates (Scott et al. 1999). Pendrin allows and homeostasis is dependent on the concentration of the mutual exchange of I-, Cl-, HCO -, HCOO- anions in H+ and HCO -. The hydrogen anions are actively trans- the inner ear, thyroid gland, and kidneys (Everett et al. ported to endolymph by H+-ATPase (Karet et al. 1999). 1997; Royaux et al. 2001). Mutations in pendrin-encoding The transport of HCO - is provided by pendrin through gene may cause syndromic (Pendred Syndrome) or the exchange of chlorine anions (Scott et al. 1999). The nonsyndromic hearing loss in connection with Enlarged damaged pendrin leads to the reduction of HCO -, and Vestibular Aqueduct – EVA or Mondini Dysplasia (Ev- thus increasing the acidity of the endolymph. The endol- erett et al. 1997; Usami et al. 1999).
ymph acidity inhibits pH-sensitive TRPV5 and TRPV6 The role of pendrin in the inner ear. Pendrin is
Ca2+ channels (Transient Receptor Potential Vanilloid). expressed in several cell types of the inner ear, e.g. in- This subsequently leads to a reduced reabsorption of ner and outer hair cells, Deiter's and Claudius' cells, the calcium ions and their increased concentration spindle-shaped cel s of the stria vascularis, prominentia in the endolymph. This mechanism probably results spiralis, and external sulcus cel s (Royaux et al. 2003; in vestibular dysfunction, degeneration of hair cel s, Wangemann et al. 2004; Yoshino et al. 2004, 2006). In and hearing loss (Nakaya et al. 2007; Wangemann et the vestibular apparatus, the pendrin is located in the apical membrane of epithelial cel s of the utriculus, sac- Role of pendrin in the thyroid gland. In the thyroid
culus, and ampul a as well as ductus and saccus endol- gland, the pendrin provides transport of iodine anions ymphaticus (Royaux et al. 2003; Yoshino et al. 2004). In to the lumen of thyroid follicles. Iodides are actively cap- Fig. 3. transport of iodide ion by nIs iodide pump into a follicular cell and pendrin into the follicular lumen followed by sub-
sequent organification and binding into t3, t4.
tsH-R – thyrotropin receptor, tg – thyroglobulin, DUoX – dual oxidase, tPo – thyreoperoxidase, MIt – monoiodotyrosine,
DIt – diiodotyrosine, revised according to Czarnocka (2011).
SENSORINEURAL HEARING LOSS AND ENDOCRINOPATHIES tured from the blood on the basolateral membrane and found in the East-Asian population (Park et al. 2003). transferred into the follicular cel s via the Na+/I- symport These mutations are characterized by an autosomal (NIS) (Dohan et al. 2003) (Fig. 3). This co-transport of recessive inheritance. They cause Pendred syndrome, two sodium cations and one iodide is carried out on SNHL associated with goiter (Reardon a Trembath the basis of electrochemical sodium gradient provided 1996; Campbell et al. 2001) and nonsyndromic SNHL by Na+/K+-ATPase (Filetti et al. 1999). From the apical associated with inner ear malformations, such as EVA cell membrane, iodide is released into the lumen of fol- (Enlarged Vestibular Aqueduct) or Mondini Dysplasia licles and in the presence of hydrogen peroxide (H O ) (Usami et al. 1999). Pendred syndrome is manifested is oxidized by thyreoperoxidase (TPO). The production by biallelic mutations (homozygote/compound het- of H O is provided by Ca2+ and NADPH-dependent erozygote) (Pryor et al. 2005). It may also occur due dual oxidases (DUOx1/2) (Dupuy et al. 1999). The to compound heterozygous mutations in SLC26A4 organification/iodination of tyrosine residues on the and other genes, such as gene encoding the FOxI1 thyroglobulin molecule takes place in the follicular lu- transcription factor (forkhead box) (Yang et al. 2007) men, thus producing monoiodotyrosine (MIT) and dii- or gene encoding Kir4.1 potassium channel (KCNJ10) odotyrosine (DIT). The thyreoperoxidase also catalyses (Yang et al. 2009).
the coupling of MIT and DIT into the triiodothyronine In terms of protein structure, mutations in the (T3) and triiodothyronine (T4/thyroxine), which re- SLC26A4 often cause retention of pendrin in various main coupled with the thyroglobulin in the col oid of the cell compartments, thus preventing from reaching lumen (Fig. 3). Secretion of T3 and T4 is preceded by the plasma membrane and its incorporation. The location thyroglobulin pinocytosis into the follicular cel s. After- of a mutated protein in cell varies according to the in- wards, T3 and T4 are separated from the thyroglobulin dividual mutation (Yoon et al. 2008). For example, the and secreted into the bloodstream. The unspent MIT most widespread mutation in Caucasoid population and DIT are enzymatical y degraded into the iodtyrosine (L236P) causes retention of pendrin in the centrosomal by dehalogenase 1 (Gnidehou et al. 2004).
region, while other mutation most often found in East Pendrin in the apical membrane of the follicular Asia (H723R) causes arresting of mutated protein in the cel s allows an exchange of iodide and chloride anions endoplasmic reticulum. These mutations mostly lead to between the follicular lumen and cel s (Yoshida et al. an incorrect composition of protein and its subsequent 2004). However, its role, as a single transporter of iodide degradation (Yoon et al. 2008). Another mutations anions in the thyroid gland, is not clear (Bizhanova and do not affect protein composition and the pendrin is Kopp 2010). Electrophysiological studies have discov- incorporated into the plasma membrane, but its trans- ered two iodide transporters on the apical side of the port function is disrupted (Taylor et al. 2002; Choi et follicular cel s (Golstein et al. 1992). Channel that could al. 2009). Loos of function SCL24A4 mutations causes participate in the outflow of iodides or exchange of the reduction in the protein activity including aminoacid Cl-/I- ions in follicles, might be a chloride channel ClCn5 substitutions and shortening of the protein (Dossena located in the apical membrane of the follicular cel s. Deficit of this channel leads to the development of goiter Mutations in the SLC26A4 gene are linked to a wide in mice (van den Hove et al. 2006).
spectrum of hearing disorders, from mild to profound Mutation in pendrin enconding gene. Pendrin is
ones (Azaiez et al. 2007). The Pendred syndrome is encoded by the SLC26A4 gene (Solute Carrier family characterized by a prelingual severe to profound bi- 26, member 4), which is located on the long arm of lateral SNHL (Reardon et al. 1997). However, in some chromosome 7 (7q22.3-q31.1) and contains 21 exons. cases, it may be fluctuating or progressive after a head For this gene more than 170 variants (Dossena et al. injury (Reardon et al. 1997; Colvin et al. 2006). For 2011b) and approximately 40 pathogenic mutations have individuals with SLC26A4 mutations, goiter usual y been described so far (Hilgert et al. 2009a). Mutations appears during puberty, but it may develop at any age are present in the promoter, exons or introns. The point or be completely missing in some individuals (Pryor substitutions are the most widespread, accounting for et al. 2005). The function of thyroid gland is variable, 64%, followed by deletions, insertions, and splice site from normal to hypothyroidism (Reardon et al. 1999). mutations, accounting for approximately 13% of the According to Bizhanova and Kopp (2010), key factor in cases (Dossena et al. 2011b). There may also be rare cases the development of goiter and hypofunction of thyroid of larger deletions, such as 4 kb long deletion (exon 3) gland in individuals suffering from Pendred syndrome SENSORINEURAL HEARING LOSS AND ENDOCRINOPATHIES is reduced intake of iodine from the food. The euthyroid Nowadays, several hundreds of mtDNA mutations individuals with biallelic SLC26A4 mutations have been are known which are responsible for the onset of a sin- reported in countries with excessive intake of iodine, gle disease or multiorgan damage. The point substitu- such as Japan and Korea (Park et al. 2003; Tsukamoto tions are the most prevalent mutation types. However, et al. 2003). Additional y, a congenital hypothyroidism a number of insertions, simple and multiple deletions, as has been reported in patients with Pendred syndrome in wel as a complex of rearrangements and inversions have regions with iodine deficiency (Gonzalez Trevino et al. also been reported (http://mitomap.org/MITOMAP). 2001). However, goiter did not develop in the SLC26A4 Based on a 10-year UK study, the minimal prevalence knock-out mice, provided iodine-deficient nutrition, of pathogenic mtDNA mutations and mitochondrial which suggests influence of other environmental, diseases has been estimated in the ratio of 12.5:100 000 epigenetic or genetic factors necessary for goiter and individuals (1:8 000) (Chinnery et al. 2000). However, hypothyroidism development in patients with Pendred another UK study reported the presence of a pathogenic syndrome (Calebiro et al. 2011; Iwata et al. 2011).
mutation that could lead to disease onset even in ratio of 1:200 individuals (Elliott et al. 2008).
snHL on the basis of mitochondrial DnA
The relationship between the genotype and phenotype is highly variable. The same mutation can cause several diseases (Maassen et al. 2005). Clinical manifestations Due to mitochondrial DNA (mtDNA) mutations, and severity of cel s and organs damages depend on syndromic or nonsyndromic SNHL may develop. The several factors. These include sorting of mitochondria mitochondrial DNA mutations account for approxi- during the cell division, rate of mutated mtDNA and mately 5% of the postlingual nonsyndromic SNHL cases energy requirements of the tissue. The mtDNA muta- (Bal ana et al. 2007).
tions cause damage predominantly in organs with high Mitochondrial DnA is double-stranded circular
energy demands. Due to high energy request and low DNA with a length of 16 569 bp encoding 37 genes. regeneration ability of hair cel s, the inner ear cochlea The mtDNA is compact, does not include introns and is sensitive to mitochondrial dysfunction. Thus SNHL the coding sequences of the adjacent genes are mainly is a frequent clinical manifestation of mitochondrial overlapping or separated by at most 1-2 non-coding diseases (Fischel-Ghodsian 2003; Kato et al. 2010). bases. It is characterized by maternal inheritance, thus Mutations of mtDNA can cause syndromic and nonsyn- a zygote during fertilization obtains mitochondria dromic SNHL and some of them may even increase the only from the ovum (DiMauro 2004). Distribution of inner ear hair cel s sensitivity to ototoxic drugs (Estivill the mitochondria from a dividing mother cell into the et al. 1998b; Hendrickx et al. 2006). Hearing loss result- daughter cel s during mitosis is general y being random. ing from mtDNA mutations probably develops due to The human cell contains 100 to 1 000 mitochondria and insufficient ATP production in stria vascularis marginal each mitochondrion contains 1 to 10 copies of mtDNA cel s. These cel s allow the active transport of K+ back to (Wal ace 1999).
endolymph via voltage-dependent potassium channels. MtDNA is characterized by a high incidence of The exact concentration and circulation of potassium mutations. Since it is present in multiple copies, one ions in individual cel s and compartments of cochlea are individual can be a carrier of both mutated and non- necessary for function of Corti organ and acoustic signal mutated mtDNAs. The occurrence of mixed wild-type transmission to the neural pathway (Wangemann 2006; and mutant mtDNA is referred as a heteroplasmy, which Olmos et al. 2011). List of mtDNA mutations leading is reported as percentage of the mutated DNA (Wal ace to SNHL is given in Table 2.
1999). The heteroplasmy level is higher in cel s with slow nonsyndromic snHL and mtDnA mutations.
and lower in tissues with fast cell division. For example, The mtDNA mutations causing nonsyndromic SNHL heteroplasmy of the buccal mucosa cel s may be even are considered as homoplasmic, when the rate of by 20% higher than in blood cel s (´t Hart et al. 1996). mutated mtDNA is above 85% in the entire mitochon- Some of the mtDNA mutations are manifested in het- drial genome (Berrettini et al. 2008). Mutations act as eroplasmic while others in homoplasmic form, with cel s a primary factor for the development of the SNHL and containing 100% of mutated mtDNA. The homoplasmic they provide predisposition to such disorder (Estivill et mutations are present in all the mtDNA copies of the al. 1998b). The most frequent mutation leading to the affected individual (Vilkki et al. 1989).
development of nonsyndromic SNHL is m.1555A>G. SENSORINEURAL HEARING LOSS AND ENDOCRINOPATHIES The table shows mitochondrial DnA mutations causing syndromic or nonsyndromic sensorineural hearing loss (snHL)
Mutation
Locus RNA
Clinical condition
References
MTRNR1 12S rRNA Nonsyndromic SNHL (Ealy et al., 2011) m.961delT/insC MTRNR1 12S rRNA Nonsyndromic SNHL (Kobayashi et al., 2005) MTRNR1 12S rRNA Nonsyndromic SNHL (Tang et al., 2002) MTRNR1 12S rRNA Nonsyndromic SNHL (Zhao et al., 2004) MTRNR1 12SrRNA Nonsyndromic SNHL (Estivill et al., 1998b) (Gutierrez Cortes et al., Nonsyndromic SNHL 2012) , (Leveque et al., 2007) (van den Ouweland et al., tRNALeu MIDD, MELAS, MERRF etc.
1994), (Fabrizi et al., 1996) (Tsukuda et al., 1997), tRNALeu diabetes mellitus, MELAS tRNASer SNHL, ataxia, myoclonus (Tiranti et al., 1995) (Pandya et al., 1999), (Brown et al., 1995) SNHL, palmoplantar (Reid et al., 1994), (Sevior et tRNASer keratoderma tRNASer Nonsyndromic SNHL (Hutchin et al., 2000) tRNASer Nonsyndromic SNHL (Sue et al., 1999b) (Arenas et al., 1999), (Sakuta tRNALys MIDD, MERRF, MELAS (Santorelli et al., 1996), (Virgilio et al., 2009) tRNAHis Nonsyndromic SNHL (Yan et al., 2011) tRNASer MIDD
(Lynn et al., 1998) m.14535_14536insMTND6 (Bannwarth et al., 2011) (Perucca-Lostanlen et al., tRNAGlu MIDD/myopathy
2002), (McFarland et al., 2004) – sensorineural hearing loss, MIDD – Maternal y Inherited Diabetes and Deafness syndrome is highlighted in bold. MELA S – Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, Stroke – like episodes; MERRF – Myoclonus Epilepsy with Ragged Red Fibres; LHON – Leber s Hereditary Optic Neuropathy. Data about the homoplasmy and heteroplasmy are taken fro The individuals with this mutation show sudden or aminoglycoside antibiotics (Estivill et al. 1998b; Rah- delayed onset of hearing loss after administration of man et al. 2012). The m.1555A>G mutation is located SENSORINEURAL HEARING LOSS AND ENDOCRINOPATHIES at a highly conserved position of the mitochondrial Maternally Inherited Diabetes and Deafness
12S rRNA gene. It causes structural changes to a small subunit of mitochondrial ribosome enabling the bind- ing and impact of aminglycosides (Forge and Schacht Maternally Inherited Diabetes and Deafness
2000; Guan 2011). However, hearing loss may absent (MIDD) syndrome is characterized by the SNHL in
in some m.1555A>G mutation carriers, which suggests connection with the diabetes mellitus. This syndrome the presence of another environmental or genetic fac- appears on the basis of mtDNA mutations and is charac- tor inducing such hearing loss (Rahman et al. 2012). terized by maternal inheritance. Six mutations have been Estimated prevalence of m.1555A>G is about 1:500 described, most of them being heteroplasmic (Table 2). (Bitner-Glindzicz et al. 2009). Data from study covering The blood heteroplasmy in individuals with the MIDD more than 7 000 individuals indicate for a more frequent syndrome vary between studies in range from 1 to 40%, (1:385) prevalence of this mutation in the Caucasoid but it may reach even 80% (van Essen et al. 2000; Maas- population (Rahman et al. 2012).
sen et al. 2005; Laloi-Michelin et al. 2009). However, it Until 2007, the mtDNA mutations causing nonsyn- is still not clear whether 1% heteroplasmy may lead to dromic SNHL had only been described in genes for a diabetic phenotype (Maassen et al. 2005).
12S rRNA and tRNASer(UCN). The screening of the entire Hearing loss associated with the MIDD syndrome mitochondrial genome of patients with nonsyndromic is sensorineural, bilateral, and progressive, and usual y hearing loss has revealed several other variants and cell becomes apparent during adolescence with typical loss culture studies have confirmed pathogenicity for one in hearing of high frequencies. Gradual y it leads to of them (m.3388C>A) (Leveque et al. 2007; Gutierrez profound hearing loss in all frequencies and progres- Cortes et al. 2012). This point substitution is found in sion varies between 1.5 and 7.9 dB per year (Yamasoba a gene encoding the ND1 subunit of complex I of mito- et al. 1996; Hendrickx et al. 2006). Diabetes mellitus of chondrial respiratory chain and causes a lower activity m.3423A>G mutation carriers is manifested in the age of the complex I (Gutierrez Cortes et al. 2012).
of 35 years in average (Maassen et al. 2004). The pen- syndromic snHL and mtDnA mutations. Syndro-
etration of this mutation is high. Diabetes develops in mic SNHL, based on the mtDNA mutations, is associated approximately 85% of carriers before the age of 70. This with a wide range of disorders. The impact of sole muta- type of diabetes is characterized by reduced glucose- tion is often manifested through various phenotypes and induced secretion of insulin, premature aging of beta syndromes. The most frequent mutation causing syndro- cel s, and absence of insulin resistance (Maassen et al. mic SNHL (m.3243A>G) mainly causes the MELAS syn- 2005). However, some studies, concerning the carriers drome (Mitochondrial myopathy, Encephalopathy, Lactic of the m.3423A>G mutation, have confirmed a hepatic Acidosis, Stroke – like episodes) or MIDD (Maternal y dysfunction (Takahashi et al. 2008) or reduced insulin Inherited Diabetes and Deafness) syndrome (van den sensitivity of skeletal muscles (Lindroos et al. 2009).
Ouweland et al. 1994). However, rarely it may cause also Most attributes indicate that the main pathological MERRF (Myoclonus Epilepsy with Ragged Red Fibres) influence is directed on the mitochondria particularly in (Fabrizi et al. 1996), PEO (maternal y inherited Progres- beta cel s (Sivitz and Yorek 2010). The mitochondria in sive External Ophtalmoplegia) (Moraes et al. 1993), KSS the pancreatic beta cel s are necessary for ATP produc- (Kearns-Sayre syndrome) or Leigh syndrome (Sue et tion, which plays a crucial role in insulin secretion. The al. 1999a). Mutation m.3243A>G is present in tRNA- glucose enters the beta cel s postprandial y by GLUT2 encoding gene, which transports leucine amino acid to transporters and its glycolysis and mitochondrial me- mitochondrial ribosomes. This mutation causes several tabolism lead to an intracel ular ATP increase. The ATP defects in the structure and function of tRNALeu(UUR). binds to the Kir6.2 subunit of K channel, closes it and For example, dysfunction of aminoacylation or reduction leads to depolarization of cell membrane. These results of tRNA processing results in a reduction of the tRNA in opening of voltage-dependent Ca2+ channels followed amount and damages its coupling with mitoribosomes by inflow of calcium ions into cel s and insulin vesicle which has impact on the translation and decreases the exocytosis is initiated (Maechler et al. 1998; Polak and ATP synthesis (Florentz et al. 2003; Olmos et al. 2011). Cave 2007). Decreased ATP production in beta cel s The syndromic SNHL is a result of several mutations probably impairs the glucose-induced insulin release present in genes encoding the transfer RNA. Other muta- into the blood circulation (Sivitz and Yorek 2010). An- tions causing syndromic SNHL are shown in Table 2.
other mechanism leading to disruption of insulin secre- SENSORINEURAL HEARING LOSS AND ENDOCRINOPATHIES tion is an increased production of free oxygen radicals a large importance in terms of the further diagnosis by mitochondria, which results in oxidative damage of and treatment. In Pendred syndrome, the hearing im- beta cel s (Green et al. 2004; Sivitz and Yorek 2010).
pairment mostly precedes clinical manifestation of the Diabetes in the MIDD syndrome is caused by the beta thyroid disease. Revealing the SLC26A4 mutation may cell dysfunction alone compared to the type 2 diabetes accelerate the diagnosis assessment of the hypothyre- where the beta cel dysfunction occurs together with the osis. When correct diagnosis is omitted, the hypothyre- insulin resistance. Therefore, medicaments targeting the osis may present a health risk for patient, especial y in insulin resistance are effective in the type 2 diabetes but situation with high demands of the thyroid hormone not in the MIDD syndrome. In addition, metformin is production. In patients with the MIDD syndrome, the contraindicated in the MIDD due to higher risk of the confirmation of the mtDNA mutation is worthy of phar- lactate acidosis development. The lactate accumulation macogenetic aspects. Diabetes mellitus in the MIDD is caused by mitochondrial damage and metabolism in patients is manifested in the adulthood by a deficiency anaerobic conditions (Murphy et al. 2008). Diet alone of the pancreatic antibodies and is often misdiagnosed or in the combination with the oral antidiabetics is as the type 2 diabetes. This incorrect diagnosis may be treatments of choice in patients with the newly mani- harmful for patient because metformin is the first line of fested diabetes in the MIDD syndrome. But progressive treatment in the type 2 diabetes, whereas in the MIDD failure of beta cel s is the cause that most of the MIDD it is not only ineffective but even increases the risk of syndrome patients will switch to the insulinotherapy the lactate acidosis development. Taken together, the earlier than the patients with type 2 diabetes (Olsson results from DNA diagnostics of the monogenic hearing et al. 1998; Maassen et al. 2004).
loss should progressively come into the routine clinical practice in the selected types of hearing impairments. In Slovakia, the DNA diagnostics of the GJB2, GJB6, and SLC26A4 genes and m.3243A>G mtDNA mutation The most frequent monogenic causes of the nonsyn- is available in the DIABGENE Laboratory (diabgene@ dromic SNHL originate due to mutations located in the connexin genes. Their identification is highly important not only in the term of classification, but particularly for the determination of the genetic risk for mutation carriers' children. Moreover, the mutation found in This work was supported by the Slovak Research and the GJB2 gene may bring better prediction of patients Development Agency grant APVV-0148-10, VEGA hearing skil s improvement after cochlear implantation. grant 1/0465/11, and Research and Development Opera- The syndromic SNHL associated with endocrinopathies tional Programme funded by the ERDF in the framework occurs less often, but proof of the genetic cause has of the project „Transendogen" (ITMS:26240220051).
Acmg. Genetics Evaluation Guidelines for the Etiologic Diagnosis of Congenital Hearing Loss. Genetic Evaluation of Congenital Hearing Loss Expert Panel. ACMG statement. Genet Med 3, 162-171, 2002.
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