Tamar Ben-Yosef

Mutations in the Gene Encoding Tight Junction Claudin-14 Cause Autosomal Recessive Deafness DFNB29

Tight junctions in the cochlear duct are thought to compartmentalize endolymph and provide structural support for the auditory neuroepithelium. The claudin family of genes is known to express protein components of tight junctions in other tissues. The essential function of one of these claudins in the inner ear was established by identifying mutations in CLDN14 that cause nonsyndromic recessive deafness DFNB29 in two large consanguineous Pakistani families. In situ hybridization and immunofluorescence studies demonstrated mouse claudin-14 expression in the sensory epithelium of the organ of Corti.

Genetic homogeneity and phenotypic variability among Ashkenazi Jews with Usher syndrome type III

Usher syndrome (USH) is an autosomal recessive disorder comprising of bilateral sensorineural hearing loss, progressive loss of vision due to retinitis pigmentosa (RP), and variable vestibular dysfunction. It is the most frequent cause of deafness and concurrent blindness in schools for the deaf-blind,1with a prevalence of 1/16 000 to 1/50 000 in various populations.2The majority of Usher syndrome cases can be clinically classified into three subtypes.3,4USH type I (USH1; OMIM 276900, 276903, 276904, 601067, 602097, 602083 and 606943) is characterised by profound prelingual sensorineural hearing loss, vestibular areflexia, and prepubertal onset of RP. USH type II (USH2; OMIM 276901, 276905 and 605472) is characterised by moderate to severe hearing impairment, no vestibular impairment, and onset of RP in the first or second decade of life. USH type III (USH3; OMIM 276902) is characterised by progressive, post-lingual hearing loss, variable onset and severity of RP, with or without vestibular dysfunction. Atypical forms of Usher syndrome associated with mutations in USH1B and USH1D have also been reported.5–7There is progression of hearing loss in some of these atypical cases, making them potentially difficult to clinically distinguish from USH3. USH3 was originally thought to be very rare, accounting for at most a few percent of the total USH population, until Pakarinen and coworkers found that up to 40% of the USH cases in Finland were consistent with USH3.4Difficulty in accurately detecting the progression of hearing loss may account for the lower frequency of reported USH3 cases outside of Finland. In the Finnish USH3 cohort, hearing loss was diagnosed before the age of 10 years in most patients, but up to the age of 40 years in some patients, with moderate to severe hearing threshold elevations at the time of detection. The mean …

Involvement of Myc targets in c-myc and N-myc induced human tumors.

The myc proto-oncogenes are transcription factors that directly regulate the expression of other genes, by binding to the specific DNA sequence, CACGTG. Among the target genes for c-Myc regulation are ECA39, p53, ornithine decarboxylase (ODC), α-prothymosin and Cdc25A. In this study we examined the involvement of c-Myc target genes in human oncogenesis induced by c-myc or N-myc. In MCF-7 breast cancer cells, the induction of c-myc expression by estrogen was followed by the induction of all the Myc targets that we examined, indicating that those genes can serve as c-Myc targets in human oncogenesis. Moreover, in breast tumors exhibiting c-myc overexpression, several Myc targets were also overexpressed. A clear correlation between the expression of c-myc and its targets was also detected in Burkitts lymphomas, which involve a specific translocation of c-myc gene, but not in other lymphoma cells. Yet, in cells derived from a neuronal origin the pattern of expression of Myc targets was more complex. In a neuroepithelioma cell line that overexpresses c-myc, only some targets were expressed. In addition in neuroblastomas, in which N-myc is amplified and overexpressed, only ODC was overexpressed in all cell lines, while all other target genes were expressed in only some of the cell lines. The more complex expression pattern found for the Myc targets in neuroblastomas suggests that genes that were identified originally as targets for c-Myc regulation may be regulated by N-Myc, but other cell specific factors are also needed for transcription of the target genes.

Recent Advances in the Understanding of Syndromic Forms of Hearing Loss

There are hundreds of different syndromes that include an auditory phenotype as a prominent feature and nearly as many reviews of this topic (Ahmed, Riazuddin, Riazuddin, & Wilcox, 2003; Griffith & Friedman, 2002; Gurtler & Lalwani, 2002; Lalwani, 2002; Morton, 2002; Petit, 2001; Steel, Erven, & Kiernan, 2002). Approximately 30% of individuals with hereditary hearing loss also have abnormalities of other organ systems and are considered to have a syndromic form of deafness (Gorlin, Toriello, & Cohen, 1995). The accompanying abnormalities range from subtle to obvious and may be congenital or delayed in appearance. The majority of these syndromes are inherited as monogenic disorders. Some of these genes have been mapped to a chromosomal map position and a subset of these mapped genes have been identified (cloned). In Table 1 we list many of the syndromic forms of hearing loss and some of the distinguishing clinical features. In many cases where hearing loss is listed as a part of a syndrome, the loss develops late and may simply be secondary to the general neurological decay. For virtually all inherited syndromic forms of hearing loss the Online Mendelian Inheritance in Man (www.ncbi.nlm.nih.gov/Omim/) has comprehensive descriptions of the clinical features and molecular genetics as well as an all-inclusive list of references. In this review we discuss only advances in our understanding of syndromic forms of deafness that have been made in the past few years. Several deafness syndromes are named after the clinician(s) who first or more fully described the disorder such as Jervell and Lange-Nielsen syndrome, Marshall syndrome, Stickler syndrome, Usher syndrome and Waardenburg syndrome (Table 1). Other hereditary deafness syndromes have been given labels that encompass part or all of the clinical presentation (phenotype) such as Branchio-Oto-Renal syndrome (abbreviated BOR, Table 1). As might be expected, there is a gene for each of these clinically distinct inherited syndromes that include hearing loss as one feature. However, there are exceptions to this generalization. Two phenotypically distinct syndromes may be due to different mutations of the same gene. Geneticists refer to different mutations of the same gene as allelic mutations or, more simply, as alleles. There are many examples of phenotypically distinct syndromes that are caused by allelic mutations such as Marshall syndrome (OMIM 154780) and Stickler syndrome type 2 (OMIM 604841), both of which can be caused by mutations of COL11A1 on chromosome 1p21 (Griffith, Sprunger, Sirko-Osadsa, Tiller, Meisler, & Warman, 1998) (Table 1). Another example is Waardenburg syndrome type 1 (OMIM 193500), Waardenburg syndrome type 3 (OMIM 148820) and Craniofacial-Deafness-Hand syndrome (OMIM 122880), which are clinically distinct but, in fact, are caused by allelic mutations of PAX3 on chromosome 2q35 (Asher, Sommer, Morell, & Friedman, 1996). Moreover, the converse is also true. Mutations of more than one gene may cause the identical clinical phenotype. This is referred to as genetic heterogeneity. For example, Usher syndrome type 1 is characterized by congenital, severe to profound hearing loss, retinitis pigmentosa (RP) with prepubertal onset and vestibular areflexia. Surprisingly, there are at least seven different genes that can cause clinically indistinguishable Usher syndrome type 1 (Table 1). Sometimes a patient has hearing loss that is obvious while their other associated abnormalities escape notice. There are many different reasons for incomplete diagnoses. Two examples illustrate this point. The hearing loss in Usher syndrome types 1 and 2 is congenital, while the onset of RP may be delayed and not noticed until adolescence. Patients who have Jervell and Lange-Nielsen syndrome are hearing impaired, but their heart conduction problems are easily overlooked (Table 1). Therefore, Section on Human Genetics (T.B.F., J.M.S., T.B-Y., A.L., E.R.W., S.R., Z.A., I.A.B.), Section on Gene Structure and Function (S.P.P, A.J.G.), and Hearing Section (S.P.P., A.J.G.), National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland; and Department of Pediatrics and Human Development (R.A.F.), Michigan State University, East Lansing, Michigan.

The R245X Mutation of PCDH15 in Ashkenazi Jewish Children Diagnosed with Nonsyndromic Hearing Loss Foreshadows Retinitis Pigmentosa

Usher syndrome is a frequent cause of the combination of deafness and blindness due to retinitis pigmentosa (RP). Five genes are known to underlie different forms of Usher syndrome type I (USH1). In the Ashkenazi Jewish population, the R245X mutation of the PCDH15 gene may be the most common cause of USH1 (Ben-Yosef T, Ness SL, Madeo AC, Bar-Lev A, Wolfman JH, Ahmed ZM, Desnick RK, Willner JP, Avraham KB, Ostrer H, Oddoux C, Griffith AJ, Friedman TB N Engl J Med 348: 1664–1670, 2003). To estimate what percentage of Ashkenazi Jewish children born with profound hearing loss will develop RP due to R245X, we examined the prevalence of the R245X PCDH15 mutation and its carrier rate among Ashkenazi Jews in Israel. Among probands diagnosed with nonsyndromic hearing loss not due to mutations of connexin 26 (GJB2) and/or connexin 30 (GJB6), and below the age of 10, 2 of 20 (10%) were homozygous for the R245X mutation. Among older nonsyndromic deaf individuals, no homozygotes were detected, although one individual was heterozygous for R245X. The carrier rate of the R245X mutation among the normal hearing Ashkenazi population in Israel was estimated at 1%. Ashkenazi Jewish children with profound prelingual hearing loss should be evaluated for the R245X PCDH15 mutation and undergo ophthalmologic evaluation to determine whether they will develop RP. Rehabilitation can then begin before loss of vision. Early use of cochlear implants in such cases may rescue these individuals from a dual neurosensory deficit.

Evidence for a founder mutation causing DFNA5 hearing loss in East Asians

Mutations in the DFNA5 gene are known to cause autosomal dominant non-syndromic hearing loss (ADNSHL). To date, five DFNA5 mutations have been reported, all of which were different in the genomic level. In this study, we ascertained a Korean family with autosomal dominant, progressive and sensorineural hearing loss and performed linkage analysis that revealed linkage to the DFNA5 locus on chromosome 7. Sequence analysis of DFNA5 identified a 3-bp deletion in intron 7 (c.991-15_991-13del) as the cause of hearing loss in this family. As the same mutation had been reported in a large Chinese family segregating DFNA5 hearing loss, we compared their DFNA5 mutation-linked haplotype with that of the Korean family. We found a conserved haplotype, suggesting that the 3-bp deletion is derived from a single origin in these families. Our observation raises the possibility that this mutation may be a common cause of autosomal dominant progressive hearing loss in East Asians.

The many faces of sensorineural hearing loss: one founder and two novel mutations affecting one family of mixed Jewish ancestry.

Dramatic progress has been made in our understanding of the highly heterogeneous molecular bases of sensorineural hearing loss (SNHL), demonstrating the involvement of all known forms of inheritance and a plethora of genes tangled in various molecular pathways. This progress permits the provision of prognostic information and genetic counseling for affected families, which might, nevertheless, be exceedingly challenging. Here, we describe an intricate genetic investigation that included Sanger-type sequencing, BeadArray technology, and next-generation sequencing to resolve a complex case involving one family presenting syndromic and nonsyndromic SNHL phenotypes in two consecutive generations. We demonstrate and conclude that such an effort can be completed during pregnancy.

Hereditary cancer and developmental abnormalities.

About 1% of all cancers are hereditary, caused by germline mutations in specific cancer-related genes. More than 25 different hereditary cancer syndromes are known, most of them involving mutations in tumor suppressor genes. These genes, which are related to cellular proliferation, might also be involved in differentiation. Hence, the phenotype of hereditary cancer syndromes might include developmental abnormalities, in addition to cancer predisposition. The information summarized here indicates that developmental phenotypes appear in both human patients and mouse models of the various hereditary cancer syndromes. These developmental abnormalities, which involve a variety of tissues and organs, usually lead to embryonic malformation that prevents the birth of viable homozygous offspring, but can also be detected in heterozygotes. In some of the syndromes a correlation exists between tumor types and developmentally affected tissues. Comparison of mice and human phenotypes from both the cancer and the developmental aspects indicates that many of the mouse models mimic the human syndromes. Our analysis indicates that most tumor suppressor genes participate not only in the regulation of cell proliferation, but also in differentiation and embryogenesis.