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An approximately 1.2-Mb bacterial artificial chromosome contig refines the genetic and physical maps of the lurcher locus on mouse chromosome 6.

ABSTRACT: Lurcher (Lc) is a semidominant mouse mutant that displays a characteristic ataxia in the heterozygous state beginning in the third postnatal week. This symptom results from a neurodegenerative event in the cerebellum: There is a catastrophic loss of Purkinje cells in the heterozygote animal between postnatal days 10 and 15. In an effort to identify the genetic lesion borne by Lc mice, we initiated a cloning project based on the position of the Lc mutation on mouse chromosome 6. We have extended our previous analysis of the genomic segment containing the Lc locus by isolating a set of stable and manipulable genomic clones called bacterial artificial chromosomes (BACs) that cover this region of mouse chromosome 6. These clones provided a good substrate for the isolation of markers that were used to refine the physical map of the locus. Furthermore, 20 of these markers were mapped onto our (B6CBACa-AW-J/A-Lc x CAST/Ei)F1 x B6CBACa-AW-J/A backcross, refining the genetic map and identifying two nonrecombinant markers (D6Rck354 and D6Rck355). These two markers, in conjunction with the closest flanking markers, were used to identify a 110-kb genomic segment that contains all four markers and hence contains the Lc locus. This small genomic segment, covered by multiple BACs, sets the stage for the final effort of this project-the identification of transcripts and of the mutation within the Lc locus.

SUBMITTER: De Jager PL

PROVIDER: S-EPMC310680 | biostudies-literature | 1997 Jul

REPOSITORIES: biostudies-literature

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An approximately 1.2-Mb bacterial artificial chromosome contig refines the genetic and physical maps of the lurcher locus on mouse chromosome 6.

De Jager P L PL Zuo J J Heintz N N

Genome research 19970701 7

Lurcher (Lc) is a semidominant mouse mutant that displays a characteristic ataxia in the heterozygous state beginning in the third postnatal week. This symptom results from a neurodegenerative event in the cerebellum: There is a catastrophic loss of Purkinje cells in the heterozygote animal between postnatal days 10 and 15. In an effort to identify the genetic lesion borne by Lc mice, we initiated a cloning project based on the position of the Lc mutation on mouse chromosome 6. We have extended ...[more]

PMID: 9253602

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Project description: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 approximately 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-D11S 1890-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 (DNA binding/EF hand/acidic 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.

Dataset Information

An approximately 1.2-Mb bacterial artificial chromosome contig refines the genetic and physical maps of the lurcher locus on mouse chromosome 6.

Publications

An approximately 1.2-Mb bacterial artificial chromosome contig refines the genetic and physical maps of the lurcher locus on mouse chromosome 6.

Similar Datasets

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