The deleterious G15498A mutation in mitochondrial DNA-encoded cytochrome b may remain clinically silent in homoplasmic carriers

Abstract

We report on a patient with severe growth retardation and IgF1 deficiency, in which a mitochondrial abnormality was suspected. An isolated mitochondrial respiratory chain complex III deficiency was found in blood lymphocytes and skin fibroblasts. Sequence analysis of the cytochrome b, which is the only mitochondrial DNA-encoded subunit of complex III, revealed a homoplasmic G15498A mutation, resulting in the substitution of a highly conserved amino acid (glycine 251 into an aspartic acid). The mutation was found to be homoplasmic in all tissues examined from the mother and her brother (lymphocytes, fibroblasts, hair roots and buccal cells). Complex III deficiency was also demonstrated in these cells. Nevertheless, the mother and the brother were asymptomatic. This mutation had been considered as a cardiomyopathy-generating mutation in a previously reported case, and its pathogenicity has been demonstrated recently in yeast. However, it seems not to fulfil the classical criteria for pathogenicity of a mitochondrial DNA mutation, especially the heteroplasmic status, and to be clinically silent, albeit present, in nonaffected relatives. We suggest that other factors are contributing to the clinical variability expression of the G15498A mtDNA mutation.

Terpestacin Inhibits Tumor Angiogenesis by Targeting UQCRB of Mitochondrial Complex III and Suppressing Hypoxia-induced Reactive Oxygen Species Production and Cellular Oxygen Sensing

“…UQCRB is known to play a pivotal role in the assembly and maintenance of Complex III, which is conserved in the respiratory chain of all aerobic organisms as well as in the electron transfer systems of chloroplasts and photosynthetic bacteria (34,35). Hereditary defects in the UQCRB gene cause several mitochondrial diseases such as hypoglycemia, lactic acidosis, myopathy, and cardiomyopathy (36,37), which are partially associated with deregulation of angiogenesis (38,39). These diverse phenotypes may arise because various genetic mutations could differentially affect the two functions of UQCRB, namely electron transfer/bioenergetics and/or O 2 -sensing functions of mitochondria.…”

Madarosis from mitochondriopathy

“…Clinically, the increase in mtDNA mutations was associated with premature ageing, weight loss, reduced subcutaneous fat, kyphosis, osteoporosis, anaemia, reduced fertility and heart failure, but also with alopecia (Trifunovic et al 2004). Another indication for dermal and hair involvement in MCP is the fact that mtDNA mutations can be also found in hair follicles, a fact which is used for diagnostic purposes (Keightley et al 2000; Haut et al 2004; Kaplanova et al 2004). In order to explain hair loss due to a respiratory chain disorder, we can speculate that the oxidative metabolism is impaired in structures responsible for the fixation, growth, stabilization and reproduction of hairs.…”

A systematic review on the biochemical threshold of mitochondrial genetic variants

“…Three cases carrying the m.15498G > A variant, a variant located near the ubiquinone binding site of complex III (Fig. 6), have been reported (Haut et al 2004). Two individuals carrying m.15498G > A variant at homoplasmic levels in lymphocytes had 43% and 57% complex III residual activities (Haut et al 2004).…”

“…6), have been reported (Haut et al 2004). Two individuals carrying m.15498G > A variant at homoplasmic levels in lymphocytes had 43% and 57% complex III residual activities (Haut et al 2004). Although the m.15498G > A variant was present at near homoplasmic levels in lymphocytes and fibroblasts with similar complex III deficiencies, one individual was phenotypically normal, whereas the other showed severe growth restriction (Haut et al 2004).…”