A patient with type 2 diabetes mellitus associated with mutations in calcium sensing receptor gene and mitochondrial DNA

A 44-year-old female with familial hypocalciuric hy. percalcemia (FHH) due to a homozygous missense mutation (Pro40Ala) in calcium sensing receptor (C aSR) gene has type 2 diabetes mellitus. The identical heterozygous mutation of CaSR gene was observed in consanguineous parents and all other family m embers examined except her two sisters. Many subjects with abnormal glucose tolerance were observed in this family, which is compatible with maternal inheritance. Mitochondrial function of complex I (NADH-coenzyme Q reductase ) activity in cybrid cells between mitochondrial DNA (mtDNA)-deleted (rho ( 0)) HeLa cells and mtDNA from the proband was decreased by 35%. The proband has eight substitutions and among these 4833 A/G is a missense substitutio n in NADH dehydrogenase 2 gene and may probably be a major pathogenic mutat ion of impaired complex I activity. These results suggest that coexistence of nuclear gene and mtDNA mutations may have caused or modified the develop ment of abnormal glucose tolerance in this family. (C) 2000 Academic Press.