Hereditary hyperekplexia, or familial startle disease (STHE), is an autosomal dominant neurologic disorder characterized by marked muscle rigidity of central nervous system origin and an exaggerated startle response to unexpected acoustic or tactile stimuli. Linkage analyses in several large families provided evidence for locus homogeneity and showed the disease gene was linked to DNA markers on the long arm of chromosome 5. Here we describe the identification of point mutations in the gene encoding the α1 subunit of the glycine receptor (GLRA1) in STHE patients from four different families. All mutations occur in the same base pair of exon 6 and result in the substitution of an uncharged amino acid (leucine or glutamine) for Arg271 in the mature protein.

Mutations in the alpha 1 subunit of the inhibitory glycine receptor cause the dominant neurologic disorder, hyperekplexia.

Cellular cholesterol metabolism is regulated primarily through the coordinate expression of two proteins, the low density lipoprotein (LDL) receptor and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (EC 1.1.1.34). We have used cDNA probes for the human genes encoding these proteins to determine the precise chromosomal location of the two loci. By in situ hybridization we have regionally mapped the LDL receptor gene, LDLR, to the short arm of chromosome 19 in bands p13.1-p13.3. This result concurs with and extends a previous study in which LDLR was mapped to chromosome 19 by screening somatic cell hybrids with a species-specific monoclonal antibody. We have assigned the HMG-CoA reductase gene, HMGCR, to chromosome 5 by Southern blotting of DNA from a somatic cell hybrid panel and to bands 5q13.3-q14 by in situ hybridizations of the cDNA probe to human metaphase cells with normal and rearranged chromosomes.

https://www.pnas.org/content/pnas/82/24/8567.full.pdf

Human genes involved in cholesterol metabolism: chromosomal mapping of the loci for the low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl-coenzyme A reductase with cDNA probes

Chinese hamster ribosomal protein S14 cDNA was used to recognize homologous human cDNA and genomic clones Human and Chinese hamster S14 protein sequences deduced from the cDNAs are identical Two overlapping human genomic S14 DNA clones were isolated from a Charon 28 placental DNA library A fragment of single-copy DNA derived from an intron region of one clone was mapped to the functional RPS14 locus on human chromosome 5q by using a panel of human X Chinese hamster hybrid cell DNAs The human S14 gene consists of five exons and four introns spanning 59 kilobase pairs of DNA Polyadenylated S14 transcripts purified from HeLa cell cytoplasma display heterogeneous 5' ends that map within noncoding RPS14 exon 1 This precludes assignment of a unique 5' boundary of RPS14 transcripts with respect to the cloned human genomic DNA Apparently HeLa cells either initiate transcription at multiple sites within RPS14 exon 1, or capped 5' oligonucleotides are removed from most S14 mRNAs posttranscription In contrast to the few murine ribosomal protein and several other mammalian housekeeping genes whose structures are known, human RPS14 contains a TATA sequence (TATACTT) upstream from exon 1 Three related short sequence motifs, also observed in murine and yeast ribosomal protein genes, occur in this region of the RPS14 gene RPS14 introns 3 and 4 both contain Alu sequences Interestingly, the Alu sequence in intron 3 is located slightly downstream from a chromosome 5 deletion breakpoint in one human X hamster hybrid clone analyzed

/pdf/primary-structure-of-human-ribosomal-protein-s14-and-the-478zf5jhw7.pdf

Primary structure of human ribosomal protein S14 and the gene that encodes it.

Comparative maps for mice and humans have been exceptionally important for predicting linkages, for identifying homologous mutations and disease loci, and for studying genome organization and evolution. This report summarizes the status of this comparative map. We provided a listing of homologous genes and anonymous loci that have been mapped in mice and humans together with references documenting homology and the chromosomal and linkage assignments (Table 1). We used a matrix to help readers find con-

/pdf/comparative-map-for-mice-and-humans-fygmq2ux5o.pdf

Comparative map for mice and humans.

Seven individuals with deletions of the distal long arm of chromosome 18 were evaluated at the clinical, cytogenetic, and molecular levels. The patients had varying degrees of typical clinical findings associated with the 18q- syndrome. Cytogenetic analysis revealed deletions from 18q21.3 or 18q22.2 to qter. Somatic cell hybrids derived from the patients were molecularly characterized using ordered groups of probes isolated from a chromosome 18-specific library. In general, the size of the deletion could be correlated with the severity of the phenotype. Based on the clinical pictures of these seven patients, a preliminary phenotypic map for the clinical features associated with deletions of the distal portion of the long arm has been generated. Furthermore, genes previously localized to 18q21 were mapped relative to the chromosome breakpoints present in these patients.

Molecular analysis of the 18q- syndrome--and correlation with phenotype

Chinese hamster-human interspecific hybrid cells, which contain human chromosome 5 and express four genes linked on that chromosome, were subjected to selective conditions requiring them to retain one of the four linked genes, leuS (encoding leucyl-tRNA synthetase), but lose another, either emtB (encoding ribosomal protein S14) or chr. Cytogenetic and biochemical analyses of spontaneous segregants isolated by using these unique selective pressures have enabled us to determine the order and regional location of the leuS, hexB, emtB, and chr genes on human chromosome 5. These segregants arise primarily by terminal deletions of various portions of the long arm of chromosome 5. Our results indicate that the order of at least three of these genes is the same on human chromosome 5 and Chinese hamster chromosome 2. Thus, there appears to be extensive homology between Chinese hamster chromosome 2 and human chromosome 5, which represents an extreme example of the conservation of gene organization between very divergent mammalian species. In addition, these hybrids and selective conditions provide a very simple and quantitative means to assess the potency of various agents suspected of inducing gross chromosomal damage.

S Dana

Papers

Selective linkage disruption in human-Chinese hamster cell hybrids: deletion mapping of the leuS, hexB, emtB, and chr genes on human chromosome 5.