MYD/Le-Os +/+ Large^myd/J

Stock number: 000300
Research areas: Developmental Biology Research, Internal/Organ Research, Neurobiology Research

Description

The semidominant oligosyndactlism (Os) mutation is maintained in repulsion with the spontaneous mutation myodystrophy(Large^myd). Myodystrophy (myd) is a spontaneous mutation in Large (like-glycosyltransferase), a glycosyltransferase involved in the glycosylation of alpha-dystroglycan. Mice homozygous for the mutation exhibit diffuse and progressive myopathy, as well as hearing loss and retinal abnormalities. This allele may be useful for studying congenital muscular dystrophy with brain and eye abnormalities (MDDGA6). Mice heterozygous for oligosyndactlism (Os) exhibit fused digits in all four feet and small kidney size.

Detailed description

Large (like-glycosyltransferase) encodes a glycosyltransferase involved in the glycosylation of alpha-dystroglycan. Mutations in LARGE are associated with congenital muscular dystrophy with brain and eye abnormalities (MDDGA6). Mice homozygous for the myodystrophy (myd) allele exhibit a short, shuffling gait, kyphosis, diffuse and progressive myopathy, myositis, cardiomyopathy and a reduced lifespan (average 17.25 weeks).

Skeletal muscle pathologies include variation in fiber size, loss of striation, centralized nuclei, calcification and nuclear rowing. Other characteristics include hearing loss, disorganized retinal layers, and axon demyelination in the peripheral nervous system.

Mice heterozygous for oligosyndactlism (Os) exhibit fused digits in all four feet, progressive diabetes, small kidney size and reduced numbers of kidney glomeruli. Homozygotes are embryonic lethal. The semidominant oligosyndactlism (Os) mutation is maintained in repulsion with the spontaneous mutation myodystrophy(Large^myd).

Development

Myodystrophy (Large^myd) arose spontaneously in 1963 at The Jackson Laboratory in the lethal spotting stock (LS/LeJ) which had been imported from University College, London in 1961. The first affected male was outcrossed to a C57BL/6J female. Matings of a homoygote times a heterozygote were carried out as often as possible or as heterozygous pairs. Close linkage was found on Chromosome 8 and oligosyndactylism (Os) was used as a marker. A Large^myd/+ male at F38 was crossed to a pintail (Pt), oligosyndactyly (Os) female of the ROP strain and after 3 sib matings an Os/+ was selected and this genotype was crossed 7 times to the +/+ members of the strain. At N7 an Os/+ was again crossed to a Large^myd/+ and the strain was maintained by sibling matings selecting the Os phenotype which was generally Os +/+ Large^myd. It was cryopreserved in 1981 by mating Os +/+ Large^myd males at N7F22 -F27 to non Os (+ +/+ ?) females.

Allele

Symbol: Os
Name: Os
MGI accession ID: MGI:1857646
Generation method: Radiation induced
Marker symbol: Os
Marker name: oligosyndactylism
Chromosome: 8
Strain of origin: (101 x C3H)F1
Molecular note: The oligosyndactylism mutation is due to a chromosomal inversion that has breakpoints approximately 10 Mb apart. One breakpoint appears to reside in the Anapc10 gene, and an aberrant transcript consisting of part of Anapc10 and an unrelated sequence is expressed at low levels.
General note: Heterozygotes are affected on all four feet. Fusion usually occurs between the second and third digits and occasionally involves the fourth (J:13049). The muscles of the forearms and lower legs as well as of the feet show anomalous arrangements not necessarily correlated with the skeletal changes (J:12944). At 11 days of gestation the preaxial border of the limbs can be seen to be reduced (J:12942), and a histological examination at this time shows that there is a small amount of cellular degeneration in the preaxial part of the footplate mesoderm, leading to coalescence of the second and third digital rudiments (J:5107). Os /+ mice have a mild diabetes insipidus present at 5 weeks and increasing with age. In combination with one or more recessive modifying genes in the selected DI stock, Os/+ mice have a severe diabetes insipidus (J:12948). The cause of the diabetes is a 45% reduction in size of the kidneys with an 80% reduction in number of glomeruli. Compensatory hypertrophy of the nephrons is not sufficient to restore normal urine-concentrating ability (J:5127)(J:5128).

Allele

Symbol: Large1^myd
Name: myodystrophy
MGI accession ID: MGI:1856965
Generation method: Spontaneous
Marker symbol: Large1
Marker name: LARGE xylosyl- and glucuronyltransferase 1
Chromosome: 8
Strain of origin: STOCK Edn3^ls
Molecular note: The mutation underlying the myodystrophy phenotype has been determined to be an intragenic deletion in the glycotransferase gene, Large. The deletion of exons 5-7 cause a frameshift and a premature stop codon before the first two catalytic domains.