ClinVar

Shimajiri et al. (2001) scanned the PAX4 gene in 200 unrelated Japanese probands with type 2 diabetes mellitus (T2D; 125853) and identified a C-T transition in exon 3, resulting in an arg121-to-trp (R121W) substitution in the PAX4 paired domain, in 6 heterozygous probands and 1 homozygous proband (mutant allele frequency 2.0%). The mutation was not found in 161 nondiabetic subjects (p = 0.01). There was a family history of diabetes or impaired glucose tolerance in 6 of the 7 mutation-positive probands. Age at diagnosis ranged from 29 to 49 years, and 4 of 7 had transient insulin therapy at the onset. The homozygous proband was a 44-year-old woman who presented at age 29 years with weight loss, fatigue, polydipsia, and polyuria, and was found to be hyperglycemic but was negative for islet cell antibodies or urine ketone bodies; she required insulin therapy within a year after diagnosis. Her mother, who was heterozygous for the mutation, had impaired glucose tolerance; oral glucose tolerance tests in her clinically asymptomatic heterozygous father and sister as well as another heterozygous carrier, son of a mutation-positive diabetic mother, showed significantly lower insulin-to-glucose ratios than those of controls (p less than 0.001). In functional studies, the R121W mutation showed 92% less suppression of PAX6 (607108) than wildtype, and almost completely lacked binding activity. In a second screening of 192 Japanese patients with type 2 diabetes, 12 heterozygotes but no homozygotes were identified (mutant allele frequency, 3.1%).