YAC Contigs of theRab1andwobbler(wr) Spinal Muscular Atrophy Gene Region on Proximal Mouse Chromosome 11 and of the Homologous Region on Human Chromosome 2p

Abstract

Despite rapid progress in the physical characterization of murine and human genomes, little molecular information is available on certain regions, e.g., proximal mouse chromosome 11 (Chr 11) and human chromosome 2p (Chr 2p). We have localized the wobbler spinal atrophy gene wr to proximal mouse Chr 11, tightly linked to Rab1, a gene coding for a small GTP-binding protein, and Glnsps1, an intronless pseudogene of the glutamine synthetase gene. We have now used these markers to construct a 1.3-Mb yeast artificial chromosome (YAC) contig of the Rab1 region on mouse Chr 11. Four YAC clones isolated from two independent YAC libraries were characterized by rare-cutting analysis, fluorescence in situ hybridization (FISH), and sequence-tagged site (STS) isolation and mapping. Rab1 and Glns-ps1 were found to be only 200 kb apart. A potential CpG island near a methylated NarI site and a trapped exon, ETG1.1, were found between these loci, and a new STS, AHY1.1, was found over 250 kb from Rab1. Two overlapping YACs were identified that contained a 150-kb region of human Chr 2p, comprising the RAB1 locus, AHY1.1, and the human homologue of ETG1.1, indicating a high degree of conservation of this region in the two species. We mapped AHY1.1 and thus human RAB1 on Chr 2p13.4-p14 using somatic cell hybrids and a radiation hybrid panel, thus extending a known region of conserved synteny between mouse Chr 11 and human Chr 2p. Recently, the gene LMGMD2B for a human recessive neuromuscular disease, limb girdle muscular dystrophy type 2B, has been mapped to 2p13-p16. The conservation between the mouse Rab1 and human RAB1 regions will be helpful in identifying candidate genes for the wobbler spinal muscular atrophy and in clarifying a possible relationship between wr and LMGMD2B.

Genetic linkage of Welander distal myopathy to chromosome 2p13

“…Two neuromuscular mutations in mouse have been mapped to regions homologous to human chromosome 2p13-the motor neuron degeneration 2 (mnd2) on mouse chromosome 6 35 and the wobbler (wr) on mouse chromosome 11. 18 The mnd2 mouse mutation causes symptoms resembling human motor neuron disease and the wr mutation causes a form of spinal muscular atrophy. 17 None of these mouse muscle disorders is a homologue of a distal myopathy.…”

“…The human dynactin p150Glued gene (DCTN1), with a proposed critical role for neural function, has through flouoresence in situ hybridization 16 and radiation hybrid mapping, been localized to 2p13. 17 The DCTN1 and the gene for the GTP-binding protein RAB1 (RAB1), with importance in vesicle fusion and transport, 18 have been screened for mutations in affected subjects and exclusion data are presented here.…”

Radiation Hybrid Mapping of Chromosomal Region 2p15–p16: Integration of Expressed and Polymorphic Sequences Maps at the Carney Complex (CNC) and Doyne Honeycomb Retinal Dystrophy (DHRD) Loci

“…Until physical mapping of this area becomes available, the RH maps reported here fill the gap of genetic information between 2p21 (6,22,27) and 2p13 (1,15,18,32). A comprehensive YAC/BAC contig of the region is now under construction in our laboratory.…”

Homology between human Chromosome 2p13.3 and the wobbler critical region on mouse Chromosome 11: comparative high-resolution mapping of STS and EST loci on YAC/BAC contigs

“…A wr critical interval between the gene for the EGF receptor (Egfr) and the microsatellite D11Mit19 has previously been defined by segregation analysis (Kaupmann et al 1992;Wedemeyer et al 1996;Korthaus et al 1996).…”