The Ds mutation arose spontaneously in the inbred DA/Hu strain at The Jackson Laboratory. Ds disrupts the orderly processes of development. Most homozygotes probably die in utero after implantation and before term (J:13012), but some may possibly be normal and viable (J:15079). Heterozygotes may be normal, may deviate slightly, or may be monstrous individuals with multiple defects (J:13012, J:2436).

Two genetics studies showed that Ds is a completely dominant gain-of-function trait (J:1477). Byusing flanking genetic markers in intercrosses between Ds/+ heterozygotes, Crosby et al. showed that homozygous Ds/Ds mice occur in the expected Mendelian frequency and that the type or severity of birth defect did not differ noticeably between affectedDs/Ds homozygotes and Ds/+ heterozygotes. In addition, they took advantage of non-disjunction in mice heterozygotes for different Robertsonian translocations to determine whether trisomic +/+/Ds mice showed defects characteristic of those found in other mice with the Disorganization defect. Discovery of Ds-specific defects in several trisomic fetuses shows that Ds is probably a gain-of-function mutation.

A statistical analysis of the number of developmental independent birth defects in affected micewith the Disorganization mutation supports a two-hit model. Because of low penetrance, most mice with Disorganization are not obviously affected. However, mice with several independent defects are found (J:2436). Crosby et al (J:39902) showed that thefrequency distribution of mice with 0, 1, 2, 3, .., defects fits a Poisson model, suggesting that inheritance of Disorganization predisposes mice to birth defects, but that other secondary somatic events must occur to determine the location and type of birth defect. The nature of this second-hit, whether genetic or epigenetic, remains to be determined.

Two groups mapped Gata4 near Ds on Chromosome 14 (J:26107, J:25626). White et al. propose that Gata4 is a candidate gene for Ds. Gata4 is on the Ds contig (N. Abbadi and J. Nadeau, unpublished), providing additional evidence that it is a candidate.

A review has been published that compares the variety of birth defects found in mice with the Disorganization mutation and with infants with similar birth defects in humans (J:44298). The possibility of a homolog of Disorganization in humans has been the subject of considerable speculation, especially given the very similar nature of some of the birth defects in the two cases. This review summarizes the cases and evaluates the evidence.

Maltese dilution, as this mutation was originally called, is an old mutation of the mouse fancy. The blue-gray color of the hair produced by this mutation in nonagouti (a/a) mice is caused by clumping of the melanin pigment into a few large masses (J:12958). The melanocytes are misshapen, with fewer and thinner dendritic processes than wild-type melanocytes, and melanin granules are largely clumped around the nucleus (J:12970). Incorporation of tyrosine into melanin proceeds at a normal rate (J:12173), and the fine structure of the melanin granules is normal (J:5346). Cultured primary melanocytesfrom dilute homozygotes are normal in morphology but display clustering of melanosomes (J:37976).

Griscelli disease (Chediak-Higashi-like syndrome, OMIM 214450) is a human autosomal recessive disorder whose symptoms include pigment dilution, immunodeficiency, and acute lethal lymphocyte and macrophage activation. Melanocyte malformation is characteristic of the pigment abnormality. The immunological abnormality includes absence of cutaneous hypersensitivity and impaired function of natural-killer cells. Griscelli disease resembles the dilute-lethal mouse mutant, except for the neurological disorder in the mouse. The locus for Griscelli disease colocalizes with the locus for myosin Va, which is mutated in at least some Griscelli patients. Griscelli disease is thus the homolog of mouse Maltese dilution (J:41253).

The original Myo5a^d mutation which identified the locuswas caused by insertion of an ecotropic murine leukemia virus (see Emv3) (J:6844, J:6587). All other mutations examined lack the virus. Reversions of Myo5a^d to wild-type, which have been reported frequently, are caused by excision of the virusleaving exactly one long terminal repeat in place (J:7092). The virus is integrated into a noncoding region of the DNA (J:7751).

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Genomic DNA is available for this strain from the Mouse DNA Resource.