Deafness Locus DFNB16 Is Located on Chromosome 15q13-q21 within a 5-cM Interval Flanked by Markers D15S994 and D15S132

Villamar, Manuela; Castillo, Ignacio del; Valle, Noelia; Romero, Lourdes; Moreno, Felipe

doi:10.1086/302321

Cited by 24 publications

(13 citation statements)

References 7 publications

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“…These data suggest that human PUNC is located distal to the critical region for DFNB16 and is therefore not a candidate gene. Recent mapping data for DFNB16 are consistent with this result and suggest that the responsible gene may be even more proximally located than originally reported (40).…”

Section: Resultssupporting

confidence: 82%

Impaired Motor Coordination in Mice That Lackpunc

Wei

Mansour

2001

Molecular and Cellular Biology

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The punc gene, encoding a member of the neural cell adhesion molecule family expressed in the developing central nervous system, limbs, and inner ear, was identified. To extend studies of the normal expression pattern of punc and to determine its function, a mouse strain bearing a lacZ/neo insertion in a 5 coding exon was created. The complex pattern of punc expression in embryos from embryonic day 9.5 (E9.5) to E11.5 was mimicked accurately by ␤-galactosidase (␤-Gal) activity. As development proceeded, the distribution of ␤-Gal activity was increasingly restricted, finally becoming confined to the brain and inner ear by E15.5. In the adult, ␤-Gal activity was detected in several regions of the inner ear and brain and was particularly strong in the cerebellar Bergmann glia. Genetic analysis of this null allele demonstrated that punc is not required for normal embryogenesis. Interestingly, comparisons of ␤-Gal activity and punc transcripts in heterozygous and homozygous mutant individuals demonstrated that punc is negatively autoregulated in some tissues. Adult puncdeficient mice were overtly normal and had normal hearing. Compared with control littermates, however, homozygous mutants had significantly reduced retention times on the Rotarod, suggesting a role for Bergmann glia-expressed Punc in the cerebellar control of motor coordination.Neural cell adhesion molecules (NCAMs) play roles in both the developing and the adult central nervous system (CNS) NCAMs have a single-pass transmembrane domain or are anchored to the cell surface via a glycosylphosphatidyl inositol linkage. Their extracellular domains contain variable numbers of immunoglobulin (Ig) and fibronectin type III (FNIII) repeats, and their intracellular domains are noncatalytic, distinguishing them from the receptor protein tyrosine kinase and phosphatase subfamilies. NCAMs participate in homophilic and/or heterophilic binding interactions and, in some cases, soluble or matrix-bound ligands have been identified. Despite the fact that NCAMs do not have catalytic activity, they are thought to participate in signaling either by extracellular interactions with catalytic subfamily members or by intracellular interactions with signal adaptors (39, 41).NCAMs have complex, dynamic, and overlapping expression patterns during nervous system development. Many family members are also expressed widely in the adult. Thus, the expression and adhesive interaction data for a given family member can only provide clues to its function. Characterization of the phenotypes of mutants has been invaluable in determining the functions of these genes. To date, the phenotypes of individuals bearing mutations in the genes encoding four different NCAMs (NCAM, L1, DCC, and contactin) have been reported in vertebrates (1,5,6,9,10,15,17,27,37,38,45). Targeted ablation of these molecules substantiated other evidence that they function during development in axon guidance, fasciculation, and cell migration and linked specific developmental events to particular NCAMs. In contrast to th...

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Section: Resultssupporting

confidence: 82%

Impaired Motor Coordination in Mice That Lackpunc

Wei

Mansour

2001

Molecular and Cellular Biology

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“…16,17 This auditory phenotype is comparable to that observed in persons with DFNB16. 27,28 CatSper and infertility in mice. These clinical presentations are consistent with the phenotypes of CatSper-null mice, which have been described in detail previously.…”

Section: Resultsmentioning

confidence: 99%

Genetic male infertility and mutation of CATSPER ion channels

et al. 2010

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“…The abundance of ␤V in the spinal cord and other neuronal tissues might offer a role for ␤V in this disorder, but again the lack of apparent phenotype in other tissues where ␤V is found reduces the likelihood of this linkage. Other possibilities include primary autosomal microcephaly (38) and autosomal recessive sensorineural hearing loss (39,40). Observations related to these conditions include the shortening of body size in C. elegans lacking sma-1 (perhaps a form of microcephaly) and the putative role of spectrin in maintaining the stiffness and function of outer hair cells (41).…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of βV Spectrin, a Mammalian Ortholog of Drosophila βHSpectrin

Stabach

Morrow

2000

Journal of Biological Chemistry

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Four mammalian ␤-spectrin genes are currently recognized, all encode proteins of Ϸ240 -280,000 M r and display 17 triple helical homologous Ϸ106-residue repeat units. In Drosophila and Caenorhabditis elegans, a variant ␤ spectrin with unusual properties has been recognized. Termed ␤ heavy (␤ H ), this spectrin contains 30 spectrin repeats, has a molecular weight in excess of 400,000, and associates with the apical domain of polarized epithelia. We have cloned and characterized from a human retina cDNA library a mammalian ortholog of Drosophila ␤ H spectrin, and in accord with standard spectrin naming conventions we term this new mammalian spectrin ␤ 5 (␤V). The gene for human ␤V spectrin (HUBSPECV) is on chromosome 15q21. The 11,722-nucleotide cDNA of ␤V spectrin is generated from 68 exons and is predicted to encode a protein with a molecular weight of 416,960. Like its fly counterpart, the derived amino acid sequence of this unusual mammalian spectrin displays 30 spectrin repeats, a modestly conserved actin-binding domain, a conserved membrane association domain 1, a conserved self-association domain, and a pleckstrin homology domain near its COOH terminus. Its putative ankyrin-binding domain is poorly conserved and may be inactive. These structural features suggest that ␤V spectrin is likely to form heterodimers and oligomers with ␣ spectrin and to interact directly with cellular membranes. Unlike its Drosophila ortholog, ␤V spectrin does not contain an SH3 domain but displays in repeat 5 a 45-residue insertion that displays 42% identity to amino acids 85-115 of the E4 protein of type 75 human papilloma virus. Human ␤V spectrin is expressed at low levels in many tissues. By indirect immunofluorescence, it is detected prominently in the outer segments of photoreceptor rods and cones and in the basolateral membrane and cytosol of gastric epithelial cells. Unlike its Drosophila ortholog, a distinct apical distribution of ␤V spectrin is inapparent in the epithelial cell populations examined, although it is confined to the outer segments of photoreceptor cells. The complete cDNA sequence of human ␤V spectrin is available from GenBank TM as accession number AF233523.First identified in association with the erythrocyte plasma membrane, spectrin is now appreciated as the central component in a ubiquitous and complex system linking membrane proteins, membrane lipids, and cytosolic factors with the major cytoskeletal filament systems of the cell. The functional unit of spectrin is typically a heterodimer composed of ␣-and ␤-type subunits joined noncovalently. Two mammalian ␣-spectrin genes are recognized, encoding ␣I and ␣II spectrin; four mammalian ␤ spectrin genes have been described, encoding ␤I-␤IV spectrin. Combinations of different ␣-and ␤-spectrins, together with diversity generated by alternative mRNA splicing, correlate with the localization of different spectrins to different cells and tissues, as well their segregation to specific intracellular compartments, including localized plasma membrane domains, the Go...

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Deafness Locus DFNB16 Is Located on Chromosome 15q13-q21 within a 5-cM Interval Flanked by Markers D15S994 and D15S132

Cited by 24 publications

References 7 publications

Impaired Motor Coordination in Mice That Lackpunc

Impaired Motor Coordination in Mice That Lackpunc

Genetic male infertility and mutation of CATSPER ion channels

Identification and Characterization of βV Spectrin, a Mammalian Ortholog of Drosophila βHSpectrin

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