A gene for autosomal dominant late-onset progressive non-syndromic hearing loss, DFNA10, maps to chromosome 6
A gene for autosomal dominant late-onset progressive non-syndromic hearing loss, DFNA10 , maps to chromosome 6 Marsha E. O'Neill1, Jacquie Marietta1, Darryl Nishimura2, Sigrid Wayne1, Guy Van Camp3, Lut Van Laer3, Clelia Negrini4, Edward R. Wilcox4, Achih Chen1, Kunihiro Fukushima1, Li Ni1, Val C. Sheffield2 and Richard J. H. Smith1,*
Departments of 1Otolaryngology and 2Pediatrics, University of Iowa, Iowa City, Iowa, 52242, USA, 3Department of Medical Genetics, University of Antwerp (UIA), 2610 Antwerpen, Belgium and 4National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland, 20850, USA
Received February 6, 1996;Revised and Accepted February 29, 1996
Late-onset non-syndromic hearing impairment is the most common type of neurological dysfunction in the elderly. It can be either acquired or inherited, although the relative impact of heredity on this type of loss is not known. To date, nine different genes have been localized, but none has been cloned. Using an extended American family in which a gene for autosomal dominant late-onset non-syndromic hearing impairment is segregating, we have identified a new locus,DFNA10, on chromosome 6.
Hearing impairment is commonly classified by audiometric criteria as conductive, sensorineural or mixed, and quantitatively graded as mild (26-40 dB), moderate (41-55 dB), moderately-severe (56-70 dB), severe (71-90 dB) or profound (>90 dB) (1 ). In addition, by medical history, it is described as congenital or late-onset, and inherited or acquired. Inherited losses are subclassified as syndromic or non-syndromic to reflect the presence or absence of co-inherited physical abnormalities (2 ).
In the United States, one in 1000 neonates has congenital severe-to-profound hearing impairment of sufficient magnitude to preclude normal speech development (3 ); in half of these affected babies, the loss is inherited. The prevalence of hearing impairment increases with age, and by puberty, the number of affected persons doubles (4 ). With advancing years, median hearing thresholds insidiously decline to such an extent that 50% of octogenarians have a hearing loss greater than 25 dB (5 ). This age-related decrease in auditory acuity makes late-onset hearing impairment the most common type of neurological dysfunction of the elderly.
Both environmental and hereditary factors impact on age-related hearing impairment, however the relative contribution of each is not known. Most types of inherited late-onset non-syndromic hearing impairment appear to be autosomal dominant. To date, nine different genes have been localized although none has been cloned (Table 1 ). Using an extended American family in which a gene for autosomal dominant late-onset progressive non-syndromic hearing impairment is segregating, we have identified a new locus, DFNA10, on chromosome 6q.
. Location and screening markers for known autosomal dominant non-syndromic genes
Locus name
Location
Screening markers
DFNA1 (6)
5q31
D5S640, D5S410, D5S412
DFNA2 (7)
1p32
D1S432, MYCL1, D1S193
DFNA3 (8)
13q12
D13S143, D13S175, D13S292
DFNA4 (9)
19q13
D19S208, D19S224, ApoC2
DFNA5 (10)
7p15
D7S629, D7S673, D7S529
DFNA6 (11)
4p15.3
D4S1614, D4S412, D4S432
DFNA7 (Tranebjærg, L., pers. comm.)
1q21-q22
D1S194, D1S196, D1S210
DFNA8 (Kirschhofer, K., pers. comm.)
15q15-q21
THBS, D15S132, D15S123
DFNA9 (12)
14q12-q13
D14S252, D14S121, D14S49
DFNA10
6q22-q23
D6S267, D6S407, D6S472
Information available online at http//:alt-www.uia.ac.be/u/dnalab/hhh/html. Nomenclature used in this table has been approved by the HUGO Nomenclature Committee, Phyllis McAlpine, PhD, FCCMG, chair.
Linkage analysis was performed on a large multi-generational family from the United States (Fig. 1 ). Affected persons exhibited an inexorably progressive sensorineural hearing loss beginning in the second-to-fifth decades and leading ultimately to severe-to-profound hearing impairment requiring the use of amplification (Fig. 2 ). After excluding known loci for non-syndromic hearing loss using markers listed on the Hereditary Hearing Loss HOMEPAGE (http//:alt-www.uia.ac.be/u/dnalab/hhh/html), a genome-wide search was initiated. Two hundred and twenty-four highly polymorphic microsatellite markers spaced at approximately 15-20 cM intervals across the genome were typed, and areas of exclusion were calculated by two-point linkage analysis using MLINK (version 5.10) of the Linkage Package (13 ).
The localization of DFNA10, defined by cross-overs, spans ~15 cM between markers D6S474 and D6S270. No obvious candidate genes have been mapped to this interval. Although regional assignments do include the laminin M chain gene (LAMM) (14 ), a nucleotide pyrophosphatase gene (NPPase) (15 ), phospholamban (16 ) and connexin43 (GJA1) (17 ), none of these genes is known to be expressed in the inner ear or to belong to gene families important in hearing (Bussoli, T., and Fleming, J., pers. comm.).
Possible animal models of DFNA10 based on synteny assignments and phenotype are the fused (Fu) and Snell's waltzer (sv) mouse mutants. The Fu phenotype is expressed in both homo- zygotes and heterozygotes and includes deafness, in addition to occasional tail shortening or kinking and a type of choreic behavior similar to, though more varied and chaotic than that of Japanese waltzing mice (18 ). The sv phenotype includes deafness, circling, hyperactivity and head tossing but expression is limited to homozygotes (19 ). The sv gene has been cloned and encodes an unconventional myosin, Myo6 (20 ). Although the homologous gene has not yet been localized in humans, the position of Myo6 on the mouse genome suggests that the human counterpart may map to a region more centromeric than the localization of DFNA10 (20 ).
The family in this study was ascertained through the University of Iowa Department of Otolaryngology-Head & Neck Surgery. A family history was obtained by questionnaire and personal interviews, and audiograms were reviewed on most persons. Blood samples were collected from cooperative family members.
Because age-of-onset of hearing loss was variable among affected persons, family members under 50 years of age who did not wear hearing aids were excluded from the linkage analysis. The portion of the extended family pedigree used to map DFNA10 to chromosome 6 was limited to normal hearing individuals over 50 years of age and affected persons with hearing aids (n = 9) or documented hearing loss (n = 2). Amplification has been recommended for the latter two persons, both of whom have moderate-to-severe sensorineural hearing impairment.
DNA was prepared from peripheral blood lymphocytes (21 ) and amplified using polymorphic microsatellite primer pairs listed in the Genome Database (GDB). Amplification was performed by the polymerase chain reaction with 30 ng template DNA, 1 [mu]l of each primer (10 [mu]M), 1 [mu]l each of 10 mM dATP, dTTP and dGTP, 1 [mu]l [32P]-dCTP together with 1 [mu]l unlabeled 0.1 mM dCTP, polymerase buffer as supplied by the vendor, and 1 U Taq DNA polymerase (Amersham) under the following conditions: denaturation at 95oC for 30 s, annealing at 55oC for 30 s, and extension at 72oC for 30 s, for a total of 25 cycles followed by a post-PCR extension step at 72oC for 10 min. Reaction products were resolved on a 6% polyacrylamide gel, followed by drying and autoradiography.
Pairwise and multipoint linkage analyses were performed using the MLINK and LODSCORE modules of version 5.10 of the Linkage Program package (13 ). All analyses were performed with recombination ratios of [theta]m/[theta]f = 1. For construction of the multipoint linkage, genotypes (version 3) were obtained from the CHLC ftp site (ftp.chlc.org). The BUILD module of CRI-MAP version 2.4 was used to construct a multipoint map using different pairs as anchors for the BUILD runs (22 ). Markers were added in decreasing order of informativeness. The same multipoint map of five markers was obtained from each of the runs. The overall support for the map was evaluated using the FLIPS option of CRI-MAP to invert pairs of adjacent loci. This five marker map was used for the multipoint linkage analysis of DFNA10 using the VITESSE version 1.0 program (23 ). Recombination distances between loci are based on reported data (24 ,25 ). The frequency of the DFNA10 gene was set at 0.001, and the disease was coded as fully penetrant and autosomal dominant.
We are indebted to the described family and thank Phyllis Weber for her help in making this study possible. This research was supported in part by a grant from the Simon and Louise Henderson Foundation (RJHS).
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