Variable penetrance of a familial progressive necrotising encephalopathy due to a novel tRNAIle homoplasmic mutation in the mitochondrial genome

Abstract

Introduction: We present a family comprising a clinically normal mother and two daughters, each with severe encephalopathy with onset in late childhood. A third daughter had died previously of an earlier onset but neuropathologically similar disease. Methods: Sequence analysis of the entire mtDNA was carried out in muscle, fibroblasts, and lymphocytes of the affected daughters and unaffected mother. Biochemical analysis of individual respiratory chain enzymes was performed on the same tissues, and on several transmitochondrial cybrid clones containing the nucleus of a 143B.206 osteosarcoma cell line and the mutant mtDNA. Results: Genetic analyses revealed in both daughters and mother the presence of a novel mutation in the tRNA Ile gene of mtDNA, which was homoplasmic in fibroblasts, lymphocytes, and skeletal muscle of the two patients. It was also homoplasmic in fibroblast and skeletal muscle samples of the mother, and approximately 97% heteroplasmic in her lymphocytes. Combined defects of complexes I and IV of the mitochondrial respiratory chain were found not only in fibroblasts of the two probands, but surprisingly also in those of their clinically unaffected mother. The respiratory chain defect segregated in transmitochondrial cybrids containing the nucleus of a 143B.206 osteosarcoma cell line and the mutant mtDNA, indicating that the latter was responsible for the biochemical phenotype. Discussion: Our results support the concept that homoplasmic mutations in tRNA genes can be responsible for mitochondrial disorders characterised by extremely variable penetrance. Albeit still unexplained, this phenomenon has important consequences in the nosological characterisation, clinical management, and genetic counselling of mitochondrial disorders.

Structural and functional role of bases 32 and 33 in the anticodon loop of yeast mitochondrial tRNAIle

“…However, several recent studies have revealed that homoplasmy, at least in somatic cells, might be a more frequent condition than what originally suggested (Lightowlers et al 1997). This is particularly striking for tRNA mutations that have been reported to be homoplasmic in both affected and nonaffected members of the same family (McFarland et al 2002;Limongelli et al 2004). In this framework, an important feature of the yeast model is that it allows the effect of mutations in homoplasmic conditions to be studied.…”

“…As an example, skeletal muscle morphology was normal, with a reduction of complexes I and IV. This substitution has been reported to have an extremely variable penetrance in the family where it was detected (Limongelli et al 2004). The three children bearing the m.4290T>C mutation had severe and fatal encephalopathy, while no data are available (e.g., about the levels of suppressor molecules) to explain the asymptomatic condition of the mother.…”

“…These are equivalent to human mutations m.4290T>C and m.4291T>C, associated with progressive encephalopathy (Limongelli et al 2004) and with a metabolic syndrome and hypomagnesaemia (Wilson et al 2004), respectively. We use the term equivalent to indicate a mutation occurring at the same position and involving the same base substitution.…”

Current Perspectives of Mitochondrial Dysfunction and Associated Diseases

“…However, milder mutations and heterogeneity can permit survival. 36 Moreover, introduction of normal mitochondrial DNA to mitochondria with mutated DNA by dynamic networking allows an efficient mechanism of mitochondria survival. 37 In addition, random distribution of mitochondria among daughter cells during cell division causes delivery of different proportions of mitochondria containing normal and mutant mitochondrial DNA to each daughter cell which further allows mitochondrial disease free survival of cells and organs.…”

“…It has been found that patients with higher mutant load have an early onset in childhood because of maternally inherited mitochondrial DNA defects. 36 This reflects the importance of the levels of heteroplasmy influencing the penetration of mitochondrial disorders.…”