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Mutations in myosin XV are responsible for congenital profound deafness DFNB3 in humans and deafness and vestibular defects in shaker 2 mice. By combining direct cDNA analyses with a comparison of 95.2 kb of genomic DNA sequence from human chromosome 17p11.2 and 88.4 kb from the homologous region on mouse chromosome 11, we have determined the genomic and mRNA structures of the human (MYO15) and mouse (Myo15) myosin XV genes. Our results indicate that full-length myosin XV transcripts contain 66 exons, are12 kb in length, and encode 365-kDa proteins that are unique among myosins in possessing very long approximately 1200-aa N-terminal extensions preceding their conserved motor domains. The tail regions of the myosin XV proteins contain two MyTH4 domains, two regions with similarity to the membrane attachment FERM domain, and a putative SH3 domain. Northern and dot blot analyses revealed that myosin XV is expressed in the pituitary gland in both humans and mice. Myosin XV transcripts were also observed by in situ hybridization within areas corresponding to the sensory epithelia of the cochlea and vestibular systems in the developing mouse inner ear. Immunostaining of adult mouse organ of Corti revealed that myosin XV protein is concentrated within the cuticular plate and stereocilia of cochlear sensory hair cells. These results indicate a likely role for myosin XV in the formation or maintenance of the unique actin-rich structures of inner ear sensory hair cells.

A major role of the peptide hormone somatostatin is inhibition of growth hormone secretion. The effects of somatostatin are mediated through five distinct G-protein-coupled receptors, each of which is expressed in the pituitary gland and other tissues. Allelic variation in the five somatostatin receptor genes (Smstr) could contribute to growth rate and overall body size. To evaluate this hypothesis we determined the chromosomal location of the Smstr genes. Restriction fragment length polymorphisms and single-strand conformational polymorphisms were used to follow the segregation of each gene in interspecific mouse backcrosses. Smstr1 through Smstr5 were localized to mouse chromosomes 12, 11, 15, 2, and 17, respectively. None of the Smstr genes colocalized with single gene mutations that affect growth. However, growth is a quantitative trait influenced by many genes and by the environment. Strains of mice selected for high and low growth have been exploited to identify chromosomal regions that modestly influence growth (J. Cheverud et a1., 1996, Genetics 142: 1305-1319). Several Smstr genes map within these regions, suggesting that they be considered candidate genes for these quantitative trait loci.

This article has been retracted at the request of the Editor-in-Chief. A co-author, who was indentified as a co-author during the submission process, had their identity removed from the author by-line during the revision process by another co-author, without any documentation that this removed co-author had received notification and/or consented. This runs contrary to Committee on Publishing Ethics (COPE) position on good publishing practice in regard to changes in authorship (see http://publicationethics.org ). This decision does not in any way reflect on the scientific findings presented in the article.

Spasmodic (spd) is a recessive mouse mutation characterized by a prolonged righting reflex, fine motor tremor, leg clasping, and stiffness. Using an intersubspecific backcross that segregates spd, we placed spd on Chr 11 with the following gene order: Adra-1-3.8 +/- 2.1 cM-Pad-1-6.3 +/- 2.7-(spd, Anx-6, Csfgm, Glr-1, Il-3, Il-4, Il-5, Sparc)-9.1 +/- 2.4-D11 Mit5-2.2 +/- 1.5-Asgr-1. This localization eliminated the alpha 1-adrenergic receptor (Adra-1) and the alpha 1 and gamma 2 subunits of the GABAA receptor as candidate genes. Two other promising candidate genes, annexin VI (Anx-6) and a glutamate receptor (Glr-1), were mapped to within 2.1 cM of the spd locus. Although no recombination was observed between spd and Anx-6 or Glr-1, no evidence was obtained for a lesion in either gene. The presence of normal Anx-6 and Glr-1 mRNA transcripts was confirmed by Northern blot analysis, in situ hybridization, and DNA sequence analysis. The localization of Anx-6 and Glr-1 extends the known synteny homology between human chromosome 5q21-q31 and mouse Chr 11 and reveals the probable chromosomal location of the human counterpart to spd. Synteny homology and phenotypic similarities suggest that spasmodic mice may be a genetic model for the inherited human startle disease, hyperekplexia (STHE).

Two nonallelic mouse mutations with severe dwarf phenotypes are characterized by a lack of growth hormone, prolactin, and thyroid stimulating hormone. The cells that normally synthesize these pituitary hormones express a common transcription factor called GHF-1 or Pit-1. Using an intersubspecific backcross, we have demonstrated tight linkage of the Pit-1 and Snell dwarf (dw) genes on mouse chromosome 16. No recombination was observed between Pit-1 and dw in 110 individuals examined. Southern blot analysis of genomic DNA reveals that the Pit-1 gene is rearranged in C3H/HeJ-dwJ/dw mice but not in coisogenic +/+ animals, providing molecular evidence that a lesion in the Pit-1 gene results in the Snell dwarf phenotype. Demonstration of low levels of Pit-1 expression in Ames dwarf (df) mice implies that both Pit-1 and df expression may be required for pituitary differentiation.

The gene for the receptor for hyaluronan-mediated motility, RHAAM (designated hyaluronan-mediated motility receptor, HMMR (human) and Hmmr (mouse), for mapping purposes), was localized to human chromosome 5q33.2-qter by somatic cell and radiation hybrid analyses. Investigation of two interspecific back-crosses localized the mouse RHAMM (Hmmr) locus 18 cM from the centromere of mouse chromosome 11 within a region of synteny homology with human chromosome 5q23-q35 genes. The map position of the human RHAMM gene places it in a region comparatively rich in disease-associated genes, including those for low-frequency hearing loss, dominant limb-girdle muscular dystrophy, diastrophic dysplasia, Treacher Collins syndrome, and myeloid disorders associated with the 5q-syndrome. The RHAMM gene location and its ability to transform cells when overexpressed implicate RHAMM as a possible candidate gene in the pathogenesis of the recently described t(5;14)(q33-q34;q11) acute lymphoblastic leukemias. 18 refs., 1 fig.

In mice and humans, growth insufficiency and male infertility are common disorders that are genetically and phenotypically complex. We describe a spontaneously arising mouse mutant, chagun, that is affected by both dwarfism and male infertility. Dwarfism disproportionately affects long bones and is characterized by a defect in the proliferative zone of chondrocytes in the growth plate. Gonads of mutant males are small, with apparent germ cell loss and no evidence of mature sperm. The locus responsible for chagun is recessive and maps to distal chromosome 9, in a region homologous to human chromosome 3. This location is consistent with chagun defining a novel locus. Identification of the mutant gene will uncover the basis for another type of skeletal dysplasia and male infertility.

The anterior lobe of the pituitary gland is composed of five hormone-producing cell types and develops from Rathke's pouch, an invagination of oral ectoderm. In mice, rapid cell proliferation occurs in the pouch from embryonic day 12.5 (e12.5) to e14.5, preceding the appearance of most hormone transcripts. Cell-type-specific commitment probably occurs prior to e14.5, but cell differentiation can be demonstrated only by detection of hormone transcripts. Although several transcription factors critical for pouch expansion are known, few of their target genes have been identified. To identify putative transcription factor target genes and cell-type-specific markers, we used differential display PCR analysis of RNA prepared from e12.5 and e14.5 Rathke's pouches. We present an expression profile of the developing pituitary gland including 83 transcripts, 40% of which are novel. The tissue distribution, cell specificity, and developmental regulation were determined for a subset of the transcripts.

We report the construction of a physical map of the region of mouse chromosome 11 that encompasses shaker-2 (sh2), a model for the human nonsyndromic deafness DFNB3. DFNB3 maps within the common deletion region of Smith-Magenis syndrome (SMS), del(17)(p11.2p11.2). Eleven of the genes mapping within the SMS common deletion region have murine homologs on the sh2 physical map. The gene order in this region is not perfectly conserved between mouse and human, a finding to be considered as we engineer a mouse model of Smith-Magenis syndrome.

We report the establishment of a high-resolution genetic map, a physical map, and a partial transcript map of the Ames dwarf critical region on mouse chromosome 11. A contig of 24 YACs and 13 P1 clones has been assembled and spans approximately 3 Mb from Flt4 to Tcf7. A library of approximately 1000 putative transcript clones from the region was prepared using exon amplification and pituitary cDNA selection. Ten novel transcripts were partially characterized, including a member of the olfactory receptor family, an alpha-tubulin-related sequence, and a novel member of the cdc2/CDC28-like kinase family, Clk4. The location of Prop1, the gene responsible for Ames dwarfism, has been localized within the contig. This contig spans a region of mouse chromosome 11 that exhibits linkage conservation with human chromosome 5q23-q35. The strength of the genetic map and genomic resources for this region suggest that comparative DNA sequencing of this region could reveal the genes responsible for other mouse mutants and human genetic diseases.

We report a high-resolution genetic map of 21 genes on the central region of mouse Chr 11. These genes were mapped by segregation analysis of more than 1650 meioses from three interspecific backcrosses. The order of these genes in mouse was compared to the previously established gene order in human. Eighteen of the 21 genes map to human Chr 5, and 2 of the genes define a proximal border for the region of homology between mouse Chr 11 and human Chr 17. Our results indicate a minimum of four rearrangements within the 10-cM region of synteny homology between mouse Chr 11 and human Chr 5. In addition, the linkage conservation is disrupted by groups of genes that map to mouse Chrs 13 and 18. These data demonstrate that large regions of conserved linkage can contain numerous chromosomal microrearrangements that have occurred since the divergence of mouse and human ancestors. Comparison of the mouse and human maps with data for other species provides an emerging picture of mammalian chromosome evolution.

The physiological role of mammalian paraoxonase/arylesterase is unknown. However, paraoxonase is an HDL-associated protein, and recent studies indicate that it may have anti-atherogenic functions. We describe the chromosomal localization and structure of the mouse paraoxonase gene (Pon1) to establish Pon1 as a candidate gene for genetically determined traits or pathological states in the mouse. The coding portion of Pon1 extends over approximately 25-26 kb and consists of nine exons and eight introns. We also present nucleotide sequences from the 5′-flanking region of Pon1 containing numerous consensus sequences for DNA binding proteins. Haplotype analysis of 94 N2 progeny from an interspecific cross indicates that Pon1 is localized on proximal mouse chromosome 6 near D6Mit86. This assignment excludes Pon1 as a candidate for the atherosclerosis susceptibility genes Ath1, Ath2, and Ath3. However, Pon1 is a promising candidate for the remaining unmapped Ath genes.

Ames dwarf (df) is an autosomal recessive mutation characterized by severe dwarfism and infertility. This mutation provides a mouse model for panhypopituitarism. The dwarf phenotype results from failure in the differentiation of the cells which produce growth hormone, prolactin, and thyroid stimulating hormone. Using the backcross (DF/B-df/df X CASA/Rk) X DF/B-df/df, we confirmed the assignment of df to mouse chromosome 11 and demonstrated recombination between df and the growth hormone gene. This backcross is an invaluable resource for screening candidate genes for the df mutation. The df locus maps to less than 1 cM distal to Pad-1 (0.85 +/- 0.85 cM). Two new genes localized on mouse chromosome 11, Rpo2-1, and Edp-1, map to a region of conserved synteny with human chromosome 17. The localization of the alpha 1 adrenergic receptor, Adra-1, extends a known region of synteny conservation between mouse chromosome 11 and human chromosome 5, and suggests that a human counterpart to df would map to human chromosome 5.