YAC contigs of the Rab1 and wobbler (wr) spinal muscular atrophy gene region on proximal mouse chromosome 11 and of the homologous region on human chromosome 2p

powerful tool to advance the identi®cation of gene com-Despite rapid progress in the physical characteriza- plexes and of disease genes. In this respect, the analysis tion of murine and human genomes, little molecular in- of human chromosomes 16 and 19 (Nowak, 1995) and formation is available on certain regions, e.g., proximal mouse chromosomes 1 (Hunter et al., 1994) and 17 (Cox mouse chromosome 11 (Chr 11) and human chromosome et al., 1993) as well as of human and murine X chromo-2p (Chr 2p). We have localized the wobbler spinal atrophy somes is particularly far advanced (Hamvas et al., 1993). gene wr to proximal mouse Chr 11, tightly linked toRab1, On the other hand, such extensive information is not a gene coding for a small GTP-binding protein, and Glns- available for mouse proximal chromosome 11 (Chr 11) ps1, an intronless pseudogene of the glutamine synthe- and human chromosome 2p (Chr 2p) (Fig. 1; cf. Berry et tase gene. We have now used these markers to construct al., 1995; Nowak, 1995), known to share at least the genesa 1.3-Mb yeast arti®cial chromosome (YAC) contig of the for the reticuloendotheliosis oncogene (Brownell et al.,Rab1 region on mouse Chr 11. Four YAC clones isolated 1985), for a brain-speci®cb-spectrin isoform (Bloom et al.,from two independent YAC libraries were characterized 1992), and for cytoplasmic malate dehydrogenase (Ball etby rare-cutting analysis, ¯uorescence in situ hybridiza-al., 1994). However, comparing the segregation map oftion (FISH), and sequence-tagged site (STS) isolation and the mouse with the human cytogenetic map, a colinearmapping. Rab1 and Glns-ps1 were found to be only 20

CHLORIDE CHANNEL-2 GENE (CLC2) MAPS TO CHROMOSOME-16 OF THE MOUSE, EXTENDING A REGION OF CONSERVED SYNTENY WITH HUMAN-CHROMOSOME-3Q

LENGELING A, GRONEMEIER M, RONSIEK M, THIEMANN A, JENTSCH TJ, Jockusch H. CHLORIDE CHANNEL-2 GENE (CLC2) MAPS TO CHROMOSOME-16 OF THE MOUSE, EXTENDING A REGION OF CONSERVED SYNTENY WITH HUMAN-CHROMOSOME-3Q. GENETICAL RESEARCH. 1995;66(02):175-178.The Clc2 gene of the mouse codes for the ubiquitously expressed chloride channel ClC-2, a member of a family of at least seven voltage gated chloride channels, some of which are implicated in hereditary diseases. Using a mouse interspecies back-cross panel, we have mapped Clc2 to Chr 16, proximal to the somatostatin gene Smst, extending a region of documented conserved synteny to human Chr 3q

Integrated radiation hybrid map of human chromosome 2p13: Possible involvement of dynactin in neuromuscular diseases

Korthaus D, Wedemeyer N, Lengeling A, Ronsiek M, Jockusch H, SchmittJohn T. Integrated radiation hybrid map of human chromosome 2p13: Possible involvement of dynactin in neuromuscular diseases. Genomics. 1997;43(2):242-244.The genes for the human neuromuscular diseases limb-girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy are located on chromosome 2p13p14, and two neuromuscular mutations of the mouse have been mapped to regions homologous to human chromosome 2p13 by conserved synteny, wobbler (wr) on proximal Chr 11 and motor neuron degeneration 2 (mnd2) on Chr 6. Neither one is a mouse homologue of LGMD2B. Recently the gene DCTN1, coding for the large subunit of the cytoskeletal protein dynactin, was shown by FISH to be located in this region and therefore should be considered a candidate for all these disease genes, Here we present mapping data based on radiation hybrid and physical mapping that more precisely define the location of nine genetic markers in the critical region and the homology relationship of human chromosome 2p with mouse proximal Chr 11 and Chr 6. The human dynactin gene was mapped between markers TGFA and D2S1394, implying that the mouse dynactin gene Dctn1 is located on Chr 6, distal to mnd2. Thus DCTN1/Dctn1 is a candidate for LGMD2B but not for mnd2 or wr. (C) 1997 Academic Press

Dynamin genes Dnm1 and Dnm2 are located on proximal mouse chromosomes 2 and 9, respectively

Klocke R, Augustin A, Ronsiek M, Stief A, vanderPutten H, Jockusch H. Dynamin genes Dnm1 and Dnm2 are located on proximal mouse chromosomes 2 and 9, respectively. GENOMICS. 1997;41(2):290-292.Dynamins, microtubule-binding GTPases, are encoded by at least three genes in mammals. Two distinct gene-specific cDNAs were used to analyze the segregation of dynamin genes Dnm1 and Dnm2 in a mouse interspecies backcross. The nervous system expressed gene Dnm1 was localized to Chr 2 between the genes for vimentin and nebulin, within a chromosomal region of conserved synteny to human chromosome 9q, consistent with the localization of the human dynamin-1 gene by FISH (see accompanying paper by Newman-Smith et al., 1997, Genomics 41: 286-289). The ubiquitously expressed Dnm2 gene was found to be closely linked to the intercellular adhesion molecule-1 gene, Icam1, in a region with homologies to human chromosomes 19p, 8q, and 11q. Potential relations of both loci to disease genes are discussed. (C) 1997 Academic Press

The protein kinase N (PKN) gene PRKCL1/Prkcl1 maps to human chromosome 19p12-p13.1 and mouse chromosome 8 with close linkage to the myodystrophy (myd) mutation

Bartsch JW, Mukai H, Takahashi N, et al. The protein kinase N (PKN) gene PRKCL1/Prkcl1 maps to human chromosome 19p12-p13.1 and mouse chromosome 8 with close linkage to the myodystrophy (myd) mutation. Genomics. 1998;49(1):129-132.Protein kinase N (PKN) is a fatty acid- and Rho-activated serine/threonine protein kinase involved in the regulation of cell motility by association with cytoskeletal components such as neurofilament and cu-actinin. We determined the chromosomal location of the human PKN gene PRKCL1 by fluorescence in situ hybridization and by radiation hybrid mapping. The corresponding mouse gene Prkcl1 was mapped by segregation analysis. We found by FISH that PRKCL1 is localized to chromosome 19p12-p13.1 and, more precisely, by radiation hybrid mapping, about 11 cR from EST WI-6344 in subband 19p12. Prkcl1 maps to mouse chromosome 8 between D8Mit6 and junb. This region of mouse Chr 8 shows a scrambled syntenic conservation to human chromosomes 4q, 8p, and 19p. As the mouse mutation myodystrophy myd has been mapped to the same region, Prkcl1 is a candidate gene for myd. (C) 1998 Academic Press

Genetic modifiers that aggravate the neurological phenotype of the wobbler mouse

Ulbrich-Lesner M, Schmidt VC, Ronsiek M, et al. Genetic modifiers that aggravate the neurological phenotype of the wobbler mouse. NEUROREPORT. 2002;13(4):535-539.The autosomal recessive mutation wobbler of the mouse (phenotype WR; genotype wr/wr) causes muscular atrophy due to motoneuron degeneration with 100% penetrance on the standard Mus musculus laboratorius C57BL/6J background. In inter- and backcrosses with M. m. castaneus strain CAST/E1 we have observed a variability in the severity of neurological symptoms. Approximately 15% of the WR (wr/wr) CAST/B6 hybrids were modified wobbler (WR*) mice defined by an aggravated neuromuscular phenotype with hindlimbs severely affected in addition to forelimbs. Histologically the overt WR* phenotype was paralleled by a caudally extended neurodegeneration in the ventral horn of the spinal cord with severe astrogliosis, and levels of acetylcholine receptor alpha-subunit m RNA in leg muscle much higher than in standard WR mice. Segregation analysis, using 68 polymorphic autosomal markers in a whole genome scan, revealed a major modifier gene locus, termed wrmodl, on chromosome 14. Individual recombination events in chromosome 14 consomic mice narrowed the wrmodl candidate region to a 29 cM interval between D14MIT154 and D14MIT105, a region homologous to human chromosome 13q. Our analysis provides access to genes that modify neurodegeneration, the human counterparts of which may be responsible for the variable expression of hereditary spinal muscular atrophies

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

Resch K, Korthaus D, Wedemeyer N, et al. 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. Mammalian genome. 1998;9(11):893-898.Human Chr 2p13-14 and homologous regions on mouse Chrs 6 and 11 have been subjects of previous studies because they comprise the loci for several neuromuscular diseases. Here we report on high-resolution mapping of 55 STS and EST loci on human Chr 2p13.3 and of 47 markers on the corresponding region on proximal mouse Chr. ii. The maps comprise several known genes, MEIS1/Meis1, RAB1a/Rab1a, MDH1/Mor2, OTX1/Otx1, and REL on human 2p13.3 and mouse Chr II, respectively, as well as the wobbler (wr) critical region of the mouse. Whereas a perfect correspondence was found in most of the 4-Mb region, a small rearrangement was discovered around the OTX1/Otx1 locus. The detailed STS and EST transcript maps of these regions and a further narrowing down of the mouse wr critical region to the interval between D11Mit79 and D11Mit19 allow for the selection of positional candidate genes for wr, and the exclusion of others