Contig Maps and Genomic Sequencing Identify Candidate Genes in the Usher 1C Locus

Michael J Higgins; Colleen D Day; Nancy J Smilinich; L Ni; Paul R Cooper; Norma J Nowak; Chris Davies; Pieter J de Jong; Fielding Hejtmancik; Glen A Evans; Richard J.H Smith; Thomas B Shows

doi:10.1101/gr.8.1.57

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Contig Maps and Genomic Sequencing Identify Candidate Genes in the Usher 1C Locus

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Contig Maps and Genomic Sequencing Identify Candidate Genes in the Usher 1C Locus

Michael J Higgins, Colleen D Day, Nancy J Smilinich, L Ni, Paul R Cooper, Norma J Nowak, Chris Davies, Pieter J de Jong, Fielding Hejtmancik, Glen A Evans, …

Genome research, Vol.8(1), pp.57-68

01/1998

DOI: 10.1101/gr.8.1.57

PMCID: PMC310690

PMID: 9445488

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Abstract

Usher syndrome 1C (USH1C) is a congenital condition manifesting profound hearing loss, the absence of vestibular function, and eventual retinal degeneration. The USH1C locus has been mapped genetically to a 2- to 3-cM interval in 11p14–15.1 between D11S899 and D11S861. In an effort to identify the USH1C disease gene we have isolated the region between these markers in yeast artificial chromosomes (YACs) using a combination of STS content mapping and Alu –PCR hybridization. The YAC contig is ∼3.5 Mb and has located several other loci within this interval, resulting in the order CEN-LDHA-SAA1-TPH-D11S1310-(D11S1888/KCNC1)-MYOD1-D11S902D11S921-D11S1890-TEL. Subsequent haplotyping and homozygosity analysis refined the location of the disease gene to a 400-kb interval between D11S902 and D11S1890 with all affected individuals being homozygous for the internal marker D11S921. To facilitate gene identification, the critical region has been converted into P1 artificial chromosome (PAC) clones using sequence-tagged sites (STSs) mapped to the YAC contig, Alu –PCR products generated from the YACs, and PAC end probes. A contig of >50 PAC clones has been assembled between D11S1310 and D11S1890, confirming the order of markers used in haplotyping. Three PAC clones representing nearly two-thirds of the USH1C critical region have been sequenced. PowerBLAST analysis identified six clusters of expressed sequence tags (ESTs), two known genes ( BIR,SUR1 ) mapped previously to this region, and a previously characterized but unmapped gene NEFA (D N A binding/ EF hand/ a cidic amino-acid-rich). GRAIL analysis identified 11 CpG islands and 73 exons of excellent quality. These data allowed the construction of a transcription map for the USH1C critical region, consisting of three known genes and six or more novel transcripts. Based on their map location, these loci represent candidate disease loci for USH1C. The NEFA gene was assessed as the USH1C locus by the sequencing of an amplified NEFA cDNA from an USH1C patient; however, no mutations were detected. [The sequence data described in this paper have been submitted to GenBank under accession numbers AC000406 – AC000407 .]

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Title: Subtitle: Contig Maps and Genomic Sequencing Identify Candidate Genes in the Usher 1C Locus
Creators: Michael J Higgins - Department of Human Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263 USA
Colleen D Day - Department of Human Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263 USA
Nancy J Smilinich - Department of Human Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263 USA
L Ni - Department of Human Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263 USA
Paul R Cooper - Department of Human Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263 USA
Norma J Nowak - Department of Human Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263 USA
Chris Davies - Department of Human Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263 USA
Pieter J de Jong - Department of Human Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263 USA
Fielding Hejtmancik - Department of Human Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263 USA
Glen A Evans - Department of Human Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263 USA
Richard J.H Smith - Department of Human Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263 USA
Thomas B Shows - Department of Human Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263 USA
Resource Type: Journal article
Publication Details: Genome research, Vol.8(1), pp.57-68
DOI: 10.1101/gr.8.1.57
PMID: 9445488
PMCID: PMC310690
NLM abbreviation: Genome Res
ISSN: 1088-9051
eISSN: 1549-5469
Publisher: Cold Spring Harbor Laboratory Press
Language: English
Date published: 01/1998
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
Record Identifier: 9984006406902771

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