Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair-cell function.

Positional cloning of hereditary deafness genes is a direct approach to identify molecules and mechanisms underlying auditory function. Here we report a locus for dominant deafness, DFNA36, which maps to human chromosome 9q13-21 in a region overlapping the DFNB7/B11 locus for recessive deafness. We identified eight mutations in a new gene, transmembrane cochlear-expressed gene 1 (TMC1), in a DFNA36 family and eleven DFNB7/B11 families. We detected a 1.6-kb genomic deletion encompassing exon 14 of Tmc1 in the recessive deafness (dn) mouse mutant, which lacks auditory responses and has hair-cell degeneration. TMC1 and TMC2 on chromosome 20p13 are members of a gene family predicted to encode transmembrane proteins. Tmc1 mRNA is expressed in hair cells of the postnatal mouse cochlea and vestibular end organs and is required for normal function of cochlear hair cells.

HPPD: A newly recognized autosomal dominant disorder involving hypertelorism, preauricular sinus, punctal pits, and deafness mapping to chromosome 14q31.

We report on a novel autosomal dominant disorder with variable phenotypic expression in a three-generation family; the major features include hypertelorism, preauricular sinus, deafness, and punctal pits with lacrimal-duct obstruction. We ruled out the involvement of EYA1, SIX1, and SIX5 as candidate genes by direct sequencing of their exons and by SNP-based linkage analysis. Subsequent SNP-based whole-genome genotyping and parametric multipoint linkage analysis gave lod scores >1 at 14q31 (LOD = 3.14), 11q25 (LOD = 1.87), and 8p23 (LOD = 1.18). By genotyping additional microsatellite markers at two of these three loci and using an expanded phenotype definition, the LOD at 14q31 increased to 3.34. Direct sequencing of the gene exons within the 14q31 critical interval and a custom aCGH experiment did not show any pathogenic mutation or copy-number changes. Further sequencing of 21 kb of promoter regions showed a novel polymorphism 1,249 bp upstream from the SELIL start codon that segregated with the disease haplotype. Cloning the novel polymorphism into luciferase reporter constructs resulted in a 20% reduction in the expression levels. The identification of this family with a distinctive clinical phenotype and linkage to a novel locus at 14q31 supports the existence of a new syndrome of the branchial cleft.

Multi-site diagnosis and management of 260 patients with auditory neuropathy/dys-synchrony (auditory neuropathy spectrum disorder).

Test results and management data are summarized for 260 patients with diagnoses of Auditory Neuropathy Spectrum Disorder (ANSD). Hearing aids were tried in 85 of these patients, and 49 patients tried cochlear implants. Approximately 15% reported some benefit from hearing aids for language learning, while improvement in speech comprehension and language acquisition was reported in 85% of patients who were implanted. Approximately 5% (13/260) of the total population developed normal speech and language without intervention. Patients were diagnosed at our laboratory (n=66) or referred from other sites (n=194), and all showed absent/grossly abnormal auditory brainstem responses (ABR), often 'ringing' cochlear microphonics, and the presence or history of otoacoustic emissions. Etiologies and co-existing conditions included genetic (n=41), peripheral neuropathies (n=20), perinatal jaundice and/or anoxia and/or prematurity (n=74). These patients comprise 10% or more of hearing impaired patients; their language acquisition trajectories are generally unpredictable from their audiograms.

The role of the dopamine transporter (DAT) in the development of PTSD in preschool children.

Population-based association studies have supported the heritability of posttraumatic stress disorder (PTSD). This study explored the influence of genetic variation in the dopamine transporter (DAT) 3' untranslated region variable number tandem repeat on the development of PTSD in preschool children exposed to Hurricane Katrina, diagnosed using a developmentally appropriate semistructured interview. A diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition , (DSM-IV; American Psychiatric Association, 1994), total symptoms, and specifically Criterion D symptoms were significantly more likely to be found in children with the 9 allele. This study replicates a previous finding in adults with PTSD. The specificity of this finding to the increased arousal symptoms of Criterion D suggests that dopamine and the DAT allele may contribute to one heritable path in a multifinality model of the development of PTSD.

Replication-mediated instability of the GAA triplet repeat mutation in Friedreich ataxia.

Friedreich ataxia is caused by the expansion of a polymorphic and unstable GAA triplet repeat in the FRDA gene, but the mechanisms for its instability are poorly understood. Replication of (GAA*TTC)n sequences (9-105 triplets) in plasmids propagated in Escherichia coli displayed length- and orientation-dependent instability. There were small length variations upon replication in both orientations, but large contractions were frequently observed when GAA was the lagging strand template. DNA replication was also significantly slower in this orientation. To evaluate the physiological relevance of our findings, we analyzed peripheral leukocytes from human subjects carrying repeats of similar length (8-107 triplets). Analysis of 9400 somatic FRDA molecules using small-pool PCR revealed a similar mutational spectrum, including large contractions. The threshold length for the initiation of somatic instability in vivo was between 40 and 44 triplets, corresponding to the length of a eukaryotic Okazaki fragment. Consistent with the stabilization of premutation alleles during germline transmission, we also found that instability of somatic cells in vivo and repeats propagated in E.coli were abrogated by (GAGGAA)n hexanucleotide interruptions. Our data demonstrate that the GAA triplet repeat mutation in Friedreich ataxia is destabilized, frequently undergoing large contractions, during DNA replication.

A novel mitochondrial tRNA(Leu(UUR)) mutation in a patient with features of MERRF and Kearns-Sayre syndrome.

In a patient with clinical features of both myoclonus epilepsy ragged-red fibers (MERRF) and Kearns-Sayre syndrome (KSS), we identified a novel guanine-to-adenine mitochondrial DNA (mtDNA) mutation at nucleotide 3255 (G3255A) of the tRNA(Leu(UUR)) gene. Approximately 5% of the skeletal muscle fibers had excessive mitochondria by succinate dehydrogenase histochemistry while a smaller proportion showed cytochrome c oxidase (COX) deficiency. In skeletal muscle, activities of mitochondrial respiratory chain complexes I, I + III, II + III, and IV were reduced. The G3255A transition was heteroplasmic in all tissues tested: muscle (53%), urine sediment (67%), peripheral leukocytes (22%), and cultured skin fibroblasts (< 2%). The mutation was absent in 50 control DNA samples. Single-fiber analysis revealed a higher proportion of mutation in COX-deficient RRF (94% +/- 5, n = 25) compared to COX-positive non-RRF (18% +/- 9, n = 21). The identification of yet another tRNA(Leu(UUR)) mutation reinforces the concept that this gene is a hot-spot for pathogenic mtDNA mutations.

A dominantly inherited progressive deafness affecting distal auditory nerve and hair cells.

We have studied 72 members belonging to a large kindred with a hearing disorder inherited in an autosomal dominant pattern. We used audiological, physiological, and psychoacoustic measures to characterize the hearing disorders. The initial phenotypic features of the hearing loss are of an auditory neuropathy (AN) with abnormal auditory nerve and brainstem responses (ABRs) and normal outer hair cell functions [otoacoustic emissions (OAEs) and cochlear microphonics (CMs)]. Psychoacoustic studies revealed profound abnormalities of auditory temporal processes (gap detection, amplitude modulation detection, speech discrimination) and frequency processes (difference limens) beyond that seen in hearing impairment accompanying cochlear sensory disorders. The hearing loss progresses over 10-20 years to also involve outer hair cells, producing a profound sensorineural hearing loss with absent ABRs and OAEs. Affected family members do not have evidence of other cranial or peripheral neuropathies. There was a marked improvement of auditory functions in three affected family members studied after cochlear implantation with return of electrically evoked auditory brainstem responses (EABRs), auditory temporal processes, and speech recognition. These findings are compatible with a distal auditory nerve disorder affecting one or all of the components in the auditory periphery including terminal auditory nerve dendrites, inner hair cells, and the synapses between inner hair cells and auditory nerve. There is relative sparing of auditory ganglion cells and their axons.

Mouse tales from Kresge: the deafness mouse.

Mouse models for human deafness have not only proven instrumental in the identification of genes for hereditary hearing loss, but are excellent model systems in which to examine gene function as well as the resulting pathophysiology. One mouse model for human nonsyndromic deafness is the deafness (dn) mouse, a spontaneous mutation in the curly-tail (ct) stock. The dn gene is on mouse Chromosome 19 and it was recently shown to be a novel gene called Tmc1. A mutation in Tmc1 is also found in Beethoven (Bth), which is another deaf mouse mutant. In humans, one autosomal dominant form of nonsyndromic hearing loss (DFNA36) and two autosomal recessive forms (DFNB7 and DFNB11) are associated with mutations in TMC1, the human homologue of Tmc1. The transmembrane protein encoded by this gene is required for normal cochlear hair cell function and the mouse models will facilitate the elucidation of the molecular pathway that is disrupted when mutations are present.

Genes and syndromic hearing loss.

UNLABELLED: Syndromes that are associated with hearing loss include Waardenburg, Stickler (STL), Jervell and Lange-Nielsen, Usher (USH), Alport, mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes, and sensorineural hearing loss (MELAS) and mitochondrial encephalomyopathy, myoclonus epilepsy, ragged-red fibers, and sensorineural hearing loss (MERRF). Waardenburg and STL show an autosomal dominant pattern of inheritance, while Jervell and Lange-Nielsen and USH are autosomal recessive, and Alport is usually X-linked. Mutations in specific genes that are associated with each of these syndromes have been identified, and genetic diagnostic tests are becoming available. The goal of ongoing research is to understand the functions of the proteins encoded by these genes, and develop effective therapies based on knowledge of the underlying causal mutations. LEARNING OUTCOMES: The reader will be introduced to basic genetic principles and will understand that (1) the etiology of hearing loss is usually genetic and many patients should be referred to a clinical geneticist; (2) a negative family history does not mean that the hearing loss is not genetic; (3) hearing loss may be part of a syndrome for which early detection and intervention for associated anomalies is necessary; and (4) many different mutations in a large number of genes underlie hearing loss.

Modification of depression by COMT val158met polymorphism in children exposed to early severe psychosocial deprivation.

OBJECTIVE: To examine the impact of the catechol-O-methyltransferase (COMT) val(158)met allele on depressive symptoms in young children exposed to early severe social deprivation as a result of being raised in institutions. METHODS: One hundred thirty six children from the Bucharest Early Intervention Project (BEIP) were randomized before 31 months of age to either care as usual (CAU) in institutions or placement in newly created foster care (FCG). At 54 months of age, a psychiatric assessment using the Preschool Age Psychiatric Assessment (PAPA) was completed. DNA was collected and genotyped for the COMT val(158)met polymorphism. Multivariate analysis examined the relationship between COMT alleles and depressive symptoms. RESULTS: Mean level of depressive symptoms was lower among participants with the met allele compared to those with two copies of the val allele (P<0.05). Controlling for group and gender, the rate of depressive symptoms was significantly lower among participants with the met/met or the met/val genotype [adjusted relative risk (aRR)=0.67, 95% CI=0.45, 0.99] compared to participants with the val/val genotype, indicating an intermediate impact for heterozygotes consistent with the biological impact of this polymorphism. The impact of genotype within groups differed significantly. There was a significant protective effect of the met allele on depressive symptoms within the CAU group, however there was no relationship seen within the FCG group. CONCLUSIONS: This is the first study, to our knowledge, to find evidence of a genexenvironment interaction in the setting of early social deprivation. These results support the hypothesis that individual genetic differences may explain some of the variability in recovery amongst children exposed to early severe social deprivation.

Genetic heterogeneity in Usher syndrome.

Mutations in seven different genes have been associated with Usher syndrome, and an additional four loci have been mapped. The identified genes encode myosin VIIa, harmonin (a PDZ-domain protein), cadherin 23, protocadherin 15, sans (a scaffold-like protein), usherin and clarin. Three clinical types of Usher syndrome have been described: USH1 patients have severe to profound congenital hearing loss, vestibular dysfunction, and retinal degeneration beginning in childhood, those with USH2 have moderate to severe congenital hearing loss, normal vestibular function, and later onset of retinitis pigmentosa, and USH3 patients have progressive hearing loss, which distinguishes them from the other two types. The shaker-1, waltzer, Ames waltzer, and Jackson shaker mice provide murine models for four of the genetic forms of Usher syndrome. Ongoing studies are enabling early diagnosis of Usher syndrome in children who present with hearing loss, thus providing time to prepare for the onset of visual loss.

Structure, diversity, and evolution of the 45-bp VNTR in intron 5 of the USH1C gene.

Usher syndrome type IC is a rare, autosomal recessive sensorineural disorder caused by mutations in the USH1C gene, which encodes a PDZ-domain protein named harmonin. The Acadian-specific 216G-->A mutation in exon 3 and a variant 9-repeat VNTR allele (designated VNTR(t,t)) in intron 5 are in complete linkage disequilibrium. (The usual form of the allele is referred to as VNTR(t).) To gain insight into the structure, diversity, and evolution of the VNTR, we analyzed individuals from seven different populations, as well as nonhuman primates and rodents. The 2-, 3-, and 6-repeat VNTR alleles were the most common. Four novel alleles containing 1, 5, 7, and 10 repeats were detected with frequencies of 0.002, 0.029, 0.005, and 0.001, respectively. The USH1C VNTR region is highly conserved among primates, but not between primates and rodents. Five unrelated individuals had a 3-repeat VNTR(t,t) allele. Haplotype analysis indicates that the 9-repeat VNTR(t,t) and the 3-repeat VNTR(t,t) alleles arose independently. However, the 9-repeat VNTR(t,t) and 6-repeat VNTR(t) alleles shared the same haplotype, suggesting an expansion from 6(t) to 9(t,t).

Outline of a medical genetics curriculum for internal medicine residency training programs.

To keep pace with the rapid advances in medical genetics, internal medicine residency training programs need to train internists to develop new attitudes, knowledge bases, and skill sets. Currently, such programs have no medical genetics curriculum. Thus, to set a minimum standard for genetics education in the context of training in internal medicine, the Internal Medicine Residency Training Program Genetics Curriculum Committee was formed, with members representing professional organizations of medical geneticists, internists, genetic counselors, internal medicine and genetics residency program directors, and internal medicine residents. The committee's task was to develop a concise outline of a medical genetics curriculum for residents in internal medicine in accordance with requirements of the Residency Review Committee for Internal Medicine of the Accreditation Council for Graduate Medical Education. The curriculum outline was drafted and circulated for comment. Before publication, the final document was approved by those member organizations that had a policy of approving curricula. Key learning objectives of the curriculum include appreciation of the rapid advances in genetics, the need for lifelong learning, the need for referral, and the role of genetic counselors and medical geneticists, as well as developing the ability to construct and analyze a three-generation pedigree. A wide variety of teaching methods can be useful in these regards, including didactic lectures, multimedia CD- ROMs, and clinical experience. Teaching should be related to clinical experiences whenever possible. The curriculum developed by the committee and presented in this article will assist in teaching residents the attitudes, knowledge, and skills they will require.

Early childhood hearing loss: clinical and molecular genetics. An educational slide set of the American College of Medical Genetics.

An educational slide set entitled "Early Childhood Hearing Loss: Clinical and Molecular Genetics" is offered by the American College of Medical Genetics (ACMG). The slide set is produced in Microsoft PowerPoint 2002. It is extensively illustrated and supported with teaching tools, explanations of each slide and figure, links to Internet resources, and a bibliography. The slide set is expected to be used as a resource for self-directed learning and in support of medical genetics teaching activities. The slide set is available through the ACMG (http://www.acmg.net) for $20, plus applicable tax and shipping. It is the first in a series of educational slide sets to be developed by the ACMG.