Biomedical subjects
Publications and source records attributed to H O Sweet.
A new dominant mutation, low set ears (Lse), in the mouse may be indicative of a mammalian branchial arch syndrome. This developmental anomaly of the external ear is accompanied by eye defects, retarded growth and shortened lifespan. The ear defect can be identified in 13-day embryos. Further studies will determine the effects of the Lse gene on other systems.
Gray tremor (gt) is an autosomal recessive mutation in the mouse linked to caracul (Ca) on chromosome 15. The complex mutant phenotype includes pigmentation defects, tremor, seizures, hypo- and dysmyelination in central and peripheral nervous systems, spongiform encephalopathy, and early death. The heterozygote (+/gt) is phenotypically normal but develops a mild spongiform encephalopathy from 2 months of age onward. The pigmentation and myelination disorders indicate that the gt genetic locus is active neonatally and probably earlier. This report focuses mainly on the later-expressed vacuolating disorder, which most closely mimics in tissue distribution, histopathology, and ultrastructure the spongiform encephalopathies caused by unconventional transmissible agents. This lesion was produced in genetically normal mice in a transmission experiment: of 99 neonatal mice inoculated intracerebrally with gt/gt brain homogenate, all 7 mice of three strains (BALB/cBy, C3HeB/FeJ, and C57BL/6J) allowed to survive for the unusually long interval of 682-721 days after inoculation, developed spongiform changes distributed as in the mutant phenotype. The gray tremor mutant presents a naturally occurring spongiform encephalopathy whose expression is determined by the interaction of genetic factors and a transmissible agent.
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A new dominant mutation, tight-skin (Tsk), is located on Chromosome 2, two recombination units distal to pallid (pa). Heterozygotes (Tsk/+) have tight skins with marked hyperplasia of the subcutaneous loose connective tissues, increased growth of cartilage and bone, and small tendons with hyperplasia of the tendon sheaths. In the loose connective tissue there are large accumulations of microfibrils in the intercellular space. In spite of the increased skeletal size, body weight is not increased. Increase in size of the thoracic skeleton is especially pronounced and leads to pathologic distentsion of the hollow thoracic viscera. Concentration of growth hormone in the pituitary and plasma is normal. Homozygotes (Tsk/TSK) die in utero at 7 to 8 days of gestation. We propose the hypothesis that Tsk might act by causing defective cell receptors with high affinity for a somatomedin-like factor promoting growth of cartilage, bone, and connective tissue and low affinity for a multiplication-stimulating factor promoting embryonic growth.
The mouse mutation hairy ears (Eh) originated in a neutron irradiation experiment at Oak Ridge National Laboratory. Subsequent linkage studies with Eh and other loci on Chr 15 suggested that it is associated with a chromosomal rearrangement that inhibits recombination since it shows tight linkage with several loci occupying the region extending from congenital goiter (cog) distal to caracul (Ca). We report here (1) linkage experiments confirming this effect on recombination and (2) meiotic and mitotic cytological studies that confirm the presence of a chromosomal rearrangement. The data are consistent with the hypothesis of a paracentric inversion in the distal half of Chr 15. The effect of the inversion extends over a minimum of 30 cM, taking into account the genetic data and the cytologically determined chromosomal involvement extending to the region of the telomere.
A new allelic series at the underwhite gene is described. Three of the alleles in the series--uw, uwd, and Uwdbr--arose as spontaneous mutations on different genetic backgrounds at The Jackson Laboratory. We report here the visible phenotypes and dominance hierarchy of these alleles, all of which are defined by a reduction of pigmentation in both eye and coat color. Electron microscopic analysis of retinal epithelium suggests that the primary defect is in the melanosome. The degree of severity of melanosome anomalies in the retina correlates with the degree of hypopigmentation in the coat. The perturbed gene and its gene product are unknown. We show that the uw locus is genetically distinct from Myo10, a suggested candidate gene for this mutation.
Dense incisors (din) is a new autosomal recessive mutation in the mouse that interferes with complete eruption of the incisors. The initial eruption of incisors through the gingiva does not differ in mutants and normal littermates, but subsequent further eruption of incisors is arrested in mutants. Radiographic examinations show that, because the incisors do not erupt, continued dentin formation gradually occludes the pulp chambers of these teeth creating as dense incisor. The arrested eruption of the incisor results in an anterior open bite. The pleiotropic phenotype of din/din mutant mice also includes small body size, reduced ear pinna size, and coat color dilution. The din mutation was mapped to Chr 16 near the pituitary transcription factor gene Pit1, but din is not a mutation in Pit1.
Mesenchymal dysplasia (mes) is a new autosomal recessive mouse mutation that alters normal growth of mesenchyme-derived tissues and provides a new mouse model for studying connective tissue development and defects. Mutants are characterized by preaxial polydactyly of all four feet, a shortened face, wide set eyes, domed head, and a shortened kinky tail. Multiple skeletal defects are seen in alizarin-stained specimens. Histological, areas of mineralization are found in tendons. Mutants also have increased musculature in the shoulders and hips and decreased peritoneal fat. Salivary glands, testes, and kidneys are smaller than in littermates. Mesenchymal dysplasia has been mapped to mouse chromosome (Chr) 13. These mapping crosses also confirmed that the Purkinje cell degeneration (pcd) mutation is on Chr 13.
A new X-linked dominant mutation in the mouse exhibiting preaxial polydactyly and tibial hemimelia is described and named X-linked polydactyly (Xpl). Linkage tests show that Xpl is located on the distal end of the X chromosome with the order Ta--13--jp--15--Xpl.
Progressive ankylosis, ank, a new recessive skeletal mutation causing a noninflammatory joint disease in mice is described. Preliminary observations suggest that three abnormal processes are involved: increased calcification of calcified cartilage and of joint tissues, hyperplasia of the cells and tissues of the joints, and degeneration within and around the tissues, tendons, and ligaments of the joints. The new mutation is closely linked, with about 4 percent recombination, to underwhite on chr 15.
Dilute suppressor, dsu, a new fully penetrant autosomal recessive mutation, acts by restoring melanocytes of homozygous dilute (d/d) mice to normal shape and almost normal number. This action creates a nondilute appearing coat color in dilute mice. Dilute suppressor is located on chromosome 1 linked to isocitrate dehydrogenase (Idh-I) with 6.25 +/- 3.49 percent recombination, and is not linked to dilute, which is on chromosome 9.
Osteochondrodystrophy (ocd) is a new autosomal recessive mouse mutation characterized by a short, slightly domed head, reduced body size, disproportionately shortened long bones of the legs, supination of the forefeet, and short thickened tail. Histologically, the epiphyses are thinner than normal. The columnar organization of the proliferative zone of cartilage is disorderly, with pleomorphic and occasionally necrotic chondrocytes. Osteochondrodystrophy has been mapped to a position near the centromere of mouse chromosome (Chr) 19.