No abstract

Multiple genes control the development of autoimmune diabetes both in humans and in the nonobese diabetic (NOD) strain of mouse. Previously, three insulin-dependent diabetes (Idd) genes, Idd3, Idd10, and Idd17, were localized to mouse Chromosome (Chr) 3. The B10- or B6-derived resistance alleles at Idd10 and Idd3 together provide the NOD mouse with nearly complete protection from diabetes. In the present study, the 10.2-cM region encoding Idd10 was defined further with newly developed congenic strains. A locus, located in the centromeric 2.1 cM of the 10.2 cM region, contributed to the Idd10 trait. However, this locus did not account for the full effect of Idd10, suggesting the presence of a second gene in the distal portion of the 10.2-cM region. This second gene is designated as Idd18 and is localized to a 5.1-cM region. The resolution of the originally defined Idd3 locus into at least four separate loci, Idd3, Idd10, Idd17, and Idd18, illustrates the complex polygenic nature of diabetes.

Specific rearrangements involving 3q21 and 3q26 are well documented in acute myeloid leukemia (AML). Aberrant expression of the Ecotropic virus integration-1 (EVI1) gene, located at 3q26, has been reported in individuals with AML and translocations or inversions of chromosome 3 long arm. We have studied six individuals with AML and inv(3)(q21q26) for disruptions to the EVI1 locus by in situ hybridization and long- range mapping. EVI1 transcripts have been detected in the blast cells of the two individuals available for expression studies. We derived a YAC containing the EVI1 gene and showed that it crossed the 3q26 inversion breakpoints in three of four cases examined. Pulsed field analysis detected aberrant fragments 3′ of the EVI1 gene in all six patients. The orientation of the gene was established and the locations of the breakpoints were refined by in situ hybridization using phage clones from this region.

We report on a patient with a pericentric inversion of the X chromosome, 46,Y,inv(X)(p11.2q21.3), who was referred for cytogenetic analysis because of mild mental retardation, short stature, prepubescent macro-orchidism, and submucous cleft palate. The same chromosomal abnormality was found in the proband's mother. The inverted X chromosome was late replicating in all the mother's lymphocytes studied, indicative of a likely unbalanced inversion. We show, by fluorescence in situ hybridisation (FISH) using a panel of ordered yeast artificial chromosome (YAC) clones, that the Xp breakpoint is localised in Xpl 1.23 between DXS146 and DXS255 and that the Xq breakpoint is assigned to the X-Y homologous region in Xq21.3. YACs crossing the Xp and Xq breakpoints have been identified. One of these two breakpoints could be linked to the mental retardation in this patient as many non-specific mental retardation (MRX) loci have previously been located in the pericentromeric region of the X chromosome. Morever, the elucidation at the molecular level of this rearrangement will also indicate if cleft palate or prepubescent macro-orchidism, or both, in this boy are related to one of the two X breakpoints. (7Med Genet 1998;35:146-150)