Identification of Genetic Markers Flanking the Locus for Maturity-Onset Diabetes of the Young on Human Chromosome 20

Abstract

A systematic search for genetic linkage with maturity-onset diabetes of the young (MODY) as expressed in the R.-W. pedigree has been carried out. Evidence for linkage was found with restriction-fragment-length polymorphism loci that map to human chromosome 20. Two-point linkage analysis with CRI-L1214 (D20S16) and MODY gave a log of the odds (lod) score of 4.16 at theta = 0.08. Multipoint linkage analysis with nine restriction-fragment-length polymorphism loci resulted in a lod score of 4.81 with the MODY locus in an approximately 20-cM region bounded by D20S16 and D20S14-D20S18. Examination of the pattern of MODY segregation suggests that additional factors, possibly genetic could be involved in the age of onset of the disease.

Mody

“…Although the gene responsible for MODY is tightly linked to the ADA gene, it was recognized that it was not the ADA gene itself. These results were confirmed and extended by Bowden et al (25) who in 1992 showed linkage of MODY to the marker D20S16. It took 5 years to identify the gene responsible for MODY (now called MODY1 to distinguish from other forms of MODY) in the RW pedigree.…”

Altered Insulin Secretory Responses to Glucose in Subjects with a Mutation in the MODY1 Gene on Chromosome 20

“…MODY appears to be due to a limited number of discrete genetic defects (3)(4)(5)(6)(15)(16)(17). One form of this disorder present in a large kindred, the RW family, has been shown to be linked to polymorphic DNA markers on chromosome 20q.…”

“…The diabetes status of each subject was determined by oral glucose tolerance test (OGTT) as defined by the National Diabetes Data Group (NDDG) (8). Each subject was typed with a series of DNA markers on chromosome 20q to determine whether or not he or she had inherited the extended at-risk haplotype (defined by alleles at the loci ADA, D20S17, D20S22, D20S79, and D20S4) that is associated with MODY in affected members of the RW family (3)(4)(5)(6). All the marker-positive subjects studied in this report showed the same extended at-risk haplotype, making misclassification extremely unlikely.…”

“…MODY subjects in this pedigree have varying degrees of hyperglycemia; -80% have or develop fasting hyperglycemia and -30% become insulin-requiring (2). Linkage studies have shown that the gene responsible for MODY in the RW family is the M0DY1 locus in the region of the adenosine deaminase (ADA) gene, closely linked to an anonymous chromosome 20 locus, D20S16 (3)(4)(5)(6). DNA typing from this region of chromosome 20 allows identification of members of the RW family who are at risk for the development of MODY.…”

The Genetics of NIDDM: An update

“…In this case, two groups independently linked diabetes to loci on chromosome 20q in the vicinity of the adenosine deaminase locus (55,56) in the same family. Like glucokinase, this defect appears to predominately affect /3-cell function.…”