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Учебники / Genetic Hearing Loss Willems 2004

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RJH, Djelantik B, Cremers CWRJ, Van de Heyning PH, Willems PJ. Linkage analysis of progressive hearing loss in five extended families maps the DFNA2 gene to a 1.25-Mb region on chromosome 1p. Genomics 1997; 41:70–74.

8.Marres H, van Ewijk M, Huygen P, Kunst H, van Camp G, Coucke P, Willems P, Cremers C. Inherited nonsyndromic hearing loss: an audiovestibular study in a large family with autosomal dominant progressive hearing loss related to DFNA2. Arch Otolaryngol Head Neck Surg 1997; 123:573–577.

9.Kunst H, Marres H, Huygen P, Ensink R, Van Camp G, Van Hauwe P, Coucke P, Willems P, Cremers C. Nonsyndromic autosomal dominant progressive sensorineural hearing loss: audiologic analysis of a pedigree linked to DFNA2. Laryngoscope 1998; 108:74–80.

10.Talebizadeh Z, Kelley PM, Askew JW, Beisel KW, Smith SD. Novel mutation in the KCNQ4 gene in a large kindred with dominant progressive hearing loss. Hum Mutat 1999; 14:493–501.

11.Ensink RJ, Huygen PL, Van Hauwe P, Coucke P, Cremers CW, Van Camp G. A Dutch family with progressive sensorineural hearing impairment linked to the DFNA2 region. Eur Arch Otorhinolaryngol 2000; 257:62–67.

12.Van Hauwe P, Coucke PJ, Ensink RJ, Huygen P, Cremers CWRJ, Van Camp G. Mutations in the KCNQ4 K(+) channel gene, responsible for autosomal dominant hearing loss, cluster in the channel pore region. Am J Med Genet 2000; 93:184–187.

13.Akita J, Abe S, Shinkawa H, Kimberling WJ, Usami S. Clinical and genetic features of nonsyndromic autosomal dominant sensorineural hearing loss: KCNQ4 is a gene responsible in Japanese. J Hum Genet 2001; 46:355–361.

14.De Leenheer EMR, Huygen PLM, Coucke PJ, Admiraal RJC, Van Camp G, Cremers CWRJ. Longitudinal and cross-sectional phenotype analysis in a new, large Dutch DFNA2/KCNQ4 family. Ann Otol Rhinol Laryngol 2002; 111:267–274.

15.Xia J, Liu C, Tang B, Pan Q, Huang L, Dai H, Zhang B, Xie W, Hu D, Zheng D, Shi X, Wang D, Xia K, Yu K, Liao X, Feng Y, Yang Y, Xiao J, Xie D, Huang J. Mutations in the gene encoding gap junction protein beta-3 associated with autosomal dominant hearing impairment. Nat Genet 1998; 20:370–373.

16.Kubisch C, Schroeder BC, Friedrich T, Lutjohann B, El-Amraoui A, Marlin S, Petit C, Jentsch TJ. KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness. Cell 1999; 96:437–446.

17.Coucke PJ, Van Hauwe P, Kelley PM, Kunst H, Schatteman I, Van Velzen D, Meyers J, Ensink RJ, Verstreken M, Declau F, Marres H, Kastury K, Bhasin S, McGuirt WT, Smith RJH, Cremers CWRJ, Van de Heyning P, Willems PJ, Smith SD, Van Camp G. Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families. Hum Mol Genet 1999; 8:1321–1328.

18.Van Hauwe P, Coucke PJ, Declau F, Kunst H, Ensink RJ, Marres HA, Cremers CWRJ, Djelantik B, Smith SD, Kelley P, Van de Heyning PH, Van Camp G. Deafness linked to DFNA2: one locus but how many genes? (Letter). Nat Genet 1999; 21:263.

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19.Coucke PJ, Van Laer L, Meyers J, Van Hauwe P, Ottschytsch N, Wauters JG, Kelley P, Willems PJ, Van Camp G. Identification of a new connexin gene GJA11 (CX59) using degenerate primers. GeneScreen 2000; 1:35–40.

20.Balciuniene J, Dahl N, Borg E, Samuelsson E, Koisti MJ, Pettersson U, Jazin EE. Evidence for digenic inheritance of nonsyndromic hereditary hearing loss in a Swedish family. Am J Hum Genet 1998; 63:786–793.

21.Borg E, Samuelsson E, Dahl N. Audiometric characterization of a family with digenic autosomal, dominant, progressive sensorineural hearing loss. Acta Otolaryngol 2000; 120:51–57.

22.Verhoeven K, Van Laer L, Kirschhofer K, Legan PK, Hughes DC, Schatteman I, Verstreken M, Van Hauwe P, Coucke P, Chen A, Smith RJ, Somers T, O eciers FE, Van de Heyning P, Richardson GP, Wachtler F, Kimberling WJ, Willems PJ, Govaerts PJ, Van Camp G. Mutations in the human alpha-tectorin gene cause autosomal dominant non-syndromic hearing impairment. Nat Genet 1998; 19:60–62.

23.Jentsch TJ. Neuronal KCNQ potassium channels: physiology and role in disease. Nat Rev Neurosci 2000; 1:21–30. Review.

24.Kharkovets T, Hardelin JP, Safieddine S, Schweizer M, El-Amraoui A, Petit C, Jentsch TJ. KCNQ4, a K+ channel mutated in a form of dominant deafness, is expressed in the inner ear and the central auditory pathway. Proc Natl Acad Sci USA 2000; 97:4333–4338.

25.Beisel KW, Nelson NC, Delimont DC, Fritzsch B. Longitudinal gradients of KCNQ4 expression in spiral ganglion and cochlear hair cells correlate with progressive hearing loss in DFNA2. Brain Res Mol Brain Res 2000; 82:137–149.

26.Trussell L. Mutant ion channel in cochlear hair cells causes deafness. Proc Natl Acad Sci USA 2000; 97:3786–3788.

27.Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, VanRaay TJ, Shen J, Timothy KW, Vincent GM, de Jager T, Schwartz PJ, Toubin JA, Moss AJ, Atkinson DL, Landes GM, Connors TD, Keating MT. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet 1996; 12:17–23.

28.Splawski I, Tristani-Firouzi M, Lehmann MH, Sanguinetti MC, Keating MT. Mutations in the hminK gene cause long QT syndrome and suppress IKs function. Nat Genet 1997; 17:338–340.

29.Biervert C, Schroeder BC, Kubisch C, Berkovic SF, Propping P, Jentsch TJ, Steinlein OK. A potassium channel mutation in neonatal human epilepsy. Science 1998; 279:403–406.

30.Charlier C, Singh NA, Ryan SG, Lewis TB, Reus BE, Leach RJ, Leppert M. A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. Nat Genet 1998; 18:53–55.

31.De Leenheer EMR, Ensink RJH, Kunst HPM, Marres HAM, Talebizadeh Z, Declau F, Smith SD, Usami SI, Van de Heyning PH, Van Camp G, Huygen PLM, Cremers CWRJ. DFNA2/KCNQ4 and its manifestations. In: The clinical presentation of genetic hearing impairment. Adv Otol Rhinol Laryngol. In: Basel, Karger, 2002; 61:41–46.

32.Van Hauwe P, Coucke P, Van Camp G. The DFNA2 locus for hearing

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impairment: two genes regulating K+ ion recycling in the inner ear. Br J Audiol 1999; 33:285–289.

33.Kunst H, Ensink R, Marres H, Declau F, Smith S, Djelantik B, Huygen P, Wuyts F, Van Camp G, Van de Heyning P, Cremers C. Genotype-phenotype correlation in progressive non-syndromic hearing impairment linked to the DFNA2 region on chromosome 1p34. Submitted.

34.Ackerman MJ, Clapham DE. Ion channels—basic science and clinical disease. N Engl J Med 1997; 336:1575–1586. Review.

35.Schroder RL, Jespersen T, Christophersen P, Strobaek D, Jensen BS, Olesen S. KCNQ4 channel activation by BMS-204352 and retigabine. Neuropharmacology 2001; 40:888–898.

17

COL11A2

Wyman T. McGuirt and Richard J. H. Smith

University of Iowa, Iowa City, Iowa, U.S.A.

Guy Van Camp

University of Antwerp, Antwerp, Belgium

I.INTRODUCTION

The rapidly expanding field of human genetics has uncovered a number of genes that, when mutated, lead to hereditary hearing impairment. Over 60 genes have been localized and more than 20 genes identified that are implicated in hereditary hearing impairment (1). Autosomal dominant inherited deafness genes are referred to as DFNA and autosomal recessive inherited deafness genes as DFNB. In 1997, the thirteenth locus for autosomal dominant nonsyndromic hearing loss was reported (2). We review the discovery of novel mutations in a collagen gene (COL11A2) that cause dominantly inherited, prelingual, nonsyndromic sensorineural hearing loss (DFNA13).

Interestingly, mutations in COL11A2 are also associated with two syndromic forms of hearing impairment, Stickler syndrome type 3 (autosomal dominant) and otospondylomegaepiphyseal dysplasia (OSMED syndrome, autosomal recessive) (3). This degree of phenotypic variability associated with allele variants of a single gene is well known in the field of deafness research. For example, mutations in MYO7A cause Usher syndrome type 1B, DFNB2, and DFNA11 and mutations in SLC26A4 cause Pendred syndrome and DFNB4 (1). Variability of inheritance patterns also has been reported for several deafness-causing genes including TECTA (DFNA8/12, DFNB21), GJB2 (DFNA3, DFNB1), and GJB3 (1). The mechanisms that determine genotype/phenotype correlation are not well understood and likely are related to both intracellular and extracellular protein interactions.

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In this chapter we: (1) describe the identification of a nonsyndromic form of dominantly inherited hearing loss (DFNA13); (2) detail the DFNA13 audiometric phenotype; (3) report cochlear expression patterns of Col11a2; (4) characterize the histological and audiometric changes in a Col11a2 mouse mutant model: and (5) hypothesize on the role of collagen in the tectorial membrane.

II.DFNA13 GENE LOCALIZATION AND MUTATION ANALYSIS

The original family that was studied was ascertained through the Department of Otolaryngology at the University of Iowa (2). They were Caucasian, lived in the Midwestern United States, and were of European descent. Family members underwent a history and physical examination by a clinical geneticist and otolaryngologist. Individuals had no syndromic features segregating with the hearing loss. No individuals had cleft palate and cephalometric analysis revealed normal facial proportions.

Audiometry was performed in consenting individuals and blood was available for study in 48 individuals (Fig. 1A). Linkage analysis was performed across the entire genome and produced a maximum two-point lod score of 6.4 at D6S299 (2). Reconstruction of haplotypes with markers closely linked to D6S299 allowed refinement of the DFNA13 candidate gene interval to 0.5 mega-base pairs (Mb) flanked by D6S1666 and D6S1560. A Dutch family (Fig. 1B) with a similar hearing loss phenotype was concurrently localized to the same interval with a lod score > 3.

A physical map was constructed across chromosome 6p21.3 on the centromeric side of the HLA class II region using yeast artificial chromosomes (YACs) and P1-derived artificial chromosomes (PACs). The sequence data for the majority of the critical region became available during this time as a large BAC (1033B10) was sequenced through the Sanger Centre. Three genes within the candidate region were found to be cochlear expressed: COL11A2, retinoic acid receptor-h (RXRB), and RING1. Mutations in COL11A2 also were known to cause of a variant form of Stickler syndrome (STLIII) (4).

Mutation screening of COL11A2, RXRB, and RING1 was completed by single-strand conformational polymorphism (SSCP) analysis and bidirectional sequencing of all PCR products. In the American family, a heterozygous C-to-T missense mutation in COL11A2 was discovered in exon 42 that is predicted to cause an arginine-to-cysteine substitution (Arg549Cys) in a ected individuals (Fig. 2A) (5). Segregation of the disease-causing mutation within the family was confirmed by Sfol digestion of the exon 42

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Figure 1 (A and B) Pedigree of the American and Dutch DFNA13/COL11A2 families. A ected individuals are depicted with filled symbols. Numbers indicate individuals with available audiograms.

PCR product. All 24 a ected individuals from the American DFNA13 family had hearing impairment with typical audiometric findings and were found to lack this digestion site. Analysis of the DFNA13 Dutch family revealed a heterozygous G-to-A transition in exon 31 of COL11A2 that is predicted to cause a glycine-to-glutamate substitution (Gly323Glu) in a ected individuals (Fig. 2B) (5). BsmF1 digestion analysis of the exon 31 PCR product indicated complete cosegregation with the hearing impairment in this family. Neither COL11A2 nucleotide change was found in an SSCP screen of 108 random individuals.

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Figure 2 Mutation analysis of the COL11A2 gene in the American (A) and Dutch (B) families revealed heterozygous missense mutations in exons 42 and 31, respectively.

III.COL11A2 AND HEARING LOSS

Collagen is an abundant extracellular protein comprised of approximately 18 subtypes transcribed by over 32 genes. When mutated, collagens cause a wide spectrum of clinical disease (6), including a number of types of syndromic deafness such as osteogenesis imperfecta (COL1A1, COL1A2), Stickler syndrome type 1, 2, and 3 (COL2A1, COL11A1, and COL11A2, respectively), Alport syndrome (COL4A3, COL4A4, and COL4A5), Marshall syndrome (COL11A1), and OSMED syndrome (COL11A2) (5,6).

Type XI collagen accounts for <10% of total cartilage collagen and is believed to maintain the interfibrillar spacing and fibril diameter of type II collagen (7). It is composed of three unique gene products: a-1 (COL11A1, 1p21), a-2(COL11A2, 6p21.3), and a-3(COL2A1, 12q13.11-q13.2) (8). The COL11A2 gene spans over 28 kilobases and includes 66 exons and an alternatively spliced exon in the amino terminus (8). Dominant and recessive

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disease-causing mutations in COL11A2 have been described and result in a spectrum of osteochondrodysplasias (9). The phenotypes are characterized by midface hypoplasia, a short up-turned nose with a depressed nasal bridge, prominent eyes and supraorbital ridges, cleft palate, occasional micrognathia with glossoptosis, early-onset degenerative joint disease that can be severe, and often, small stature. Hearing impairment is usually present and is generally severe and sensorineural. Notably absent, however, are the ophthalmological abnormalities seen with COL11A1 or COL2A1 mutations, reflecting the absence of COL11A2 expression in the ocular vitreous (4). The mutations that cause the DFNA13 phenotype are the only reported COL11A2 mutations that are not associated with an identifiable syndrome

(5).

IV. DFNA13 AUDIOMETRIC ANALYSIS

The congenital sensorineural hearing loss in the American family varied from mild to moderately severe in degree. Audiograms of a ected individuals showed greater midfrequency than lowor high-frequency involvement. A detailed audiometric analysis was performed on the American DFNA13 family and revealed a mean threshold of approximately 29 dB at 0.25, 0.5, and 8 kHz (10). The mean thresholds at the frequencies between 1 and 4 kHz were higher at approximately 44 dB, producing a typical U-shaped audiogram (Fig. 3A). No significant progression of hearing impairment was noted when compared to reference levels for standardized curves. Interestingly, the rate of high-frequency hearing loss typical of presbycusis was less severe in the American DFNA13 family when compared to standardized curves. The cause of this preserved high-frequency hearing in the DFNA13 American family is unclear. The onset of hearing loss was presumed to be prelingual based on history and audiograms that revealed the typical midfrequency pattern in three children under the age of 12 years.

The hearing impairment in the Dutch family has been described as midfrequency (1–2 kHz) hearing impairment, with additional impairment at the higher frequencies (6–8 kHz) (11). There is a threshold average of approximately 25 dB at 0.25, 0.5, and 4 kHz, approximately 35–40-dB threshold at 1, 2, and 6 kHz, and approximately 50 dB at 8 kHz (Fig. 3B). Hearing impairment was documented audiometrically in one child at the age of 4 years. However, consistent with the American family, most individuals were not recognized as hearing impaired until the second or third decade of life. We believe this most likely represents a failure to diagnosis mild-to-moder- ate hearing impairment at a young age rather than rapid progression of hearing loss.

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Figure 3 Age-related typical audiograms (ARTA) of the American (A) and Dutch

(B) families. Left vertical axis: decibel (SPL); right vertical axis: age in years; horizontal axis: frequency (kHz).

Caloric testing of vestibular response was also performed in 17 individuals from the Dutch kindred (11). Caloric abnormalities were found in eight of 17 (47%) individuals tested. None of these individuals had substantial vestibular symptoms. Vestibular abnormalities included unilateral vestibular hyporeflexia (n = 5), bilateral hyporeflexia (n = 2), and bilateral areflexia (n = 1). Vestibular hyperreflexia occured in four of 17 cases tested. There was a trend for the type of vestibular dysfunction to segregate among family subgroups.

V.COL11A2 EXPRESSION AND ANIMAL STUDIES

In situ hybridization studies of Col11a2 in the developing murine (C57BI/6J) cochlea were performed at E15.5, P1, and P5 (5). Col11a2 was expressed strongly in the cartilaginous otic capsule at E15.5, with diminished hybridization at later developmental stages. Hybridization to the cochlear duct was not significantly di erent from that observed with the sense probe. At P5, di use homogeneous hybridization was observed in the spiral limbus region and lateral wall of the cochlea. Col11a2 expression did not appear

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Figure 4 Light microscopy of the tectorial membrane in Col11a2-deficient mice

(A) revealed a less compact tectorial membrane than that seen in either heterozygous or wild-type littermates (B).