RESUMEN
AIMS: Mitochondrial diseases form one of the largest groups of inborn errors of metabolism. The birth prevalence is approximately 1/5000 in well-studied populations, but little has been reported from Sub-Saharan Africa. The aim of this study was to describe the genetics underlying mitochondrial disease in South Africa. METHODS: An audit was performed on all mitochondrial disease genetic testing performed in Cape Town, South Africa. RESULTS: Of 1614 samples tested for mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) variants in South Africa between 1994 and 2019, there were 155 (9.6 %) positive results. Pathogenic mtDNA variants accounted for 113 (73%)/155, from 96 families. Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes, 37 (33%)/113, Leber's hereditary optic neuropathy, 26 (23%)/113, and single large mtDNA deletions, 22 (20%)/113, accounted for 76%. Thirty eight of 42 nDNA-positive results were homozygous for the MPV17 pathogenic variant c.106C>T (p.[Gln36Ter, Ser25Profs*49]) causing infantile neurohepatopathy, one of the largest homozygous groups reported in the literature. The other nDNA variants were in TAZ1, CPT2, BOLA3 and SERAC1. None were identified in SURF1, POLG or PDHA1. CONCLUSIONS: Finding a large group with a homozygous nuclear pathogenic variant emphasises the importance of looking for possible founder effects. The absence of other widely described pathogenic nDNA variants in this cohort may be due to reduced prevalence or insufficient testing. As advances in therapeutics develop, it is critical to develop diagnostic platforms on the African subcontinent so that population-specific genetic variations can be identified.
Asunto(s)
Variación Genética , Proteínas de la Membrana/genética , Enfermedades Mitocondriales/genética , Encefalomiopatías Mitocondriales/genética , Proteínas Mitocondriales/genética , Atrofia Óptica Hereditaria de Leber/genética , Acidosis Láctica/genética , Acidosis Láctica/patología , África del Sur del Sahara , Núcleo Celular/genética , Estudios de Cohortes , Pruebas Genéticas , Homocigoto , Humanos , Mitocondrias/genética , Enfermedades Mitocondriales/patología , Encefalomiopatías Mitocondriales/patología , Mutación , Atrofia Óptica Hereditaria de Leber/patologíaRESUMEN
Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency causes episodic ketoacidosis. We encountered a case of siblings in South Africa in whom a novel homozygous mutation (R268H) was found in genomic DNA. Mutant SCOT protein was very faintly detected in their fibroblasts using immunoblot analysis. Transient expression analysis of R268H mutant cDNA at 37 degrees C revealed that the R268H mutant protein was clearly detected, as much as 50% wild-type, together with 40% residual SCOT activities, hence R268H was first regarded as not being a disease-causing mutation. Since no other mutation was identified, R268H mutation was re-evaluated by further transient expression analysis. Accumulation of the R268H mutant protein was revealed to be strongly temperature dependent; residual SCOT activities were calculated to be 59.7%, 34%, and 4%, respectively, in expression at 30 degrees C, 37 degrees C, and 40 degrees C in SV40-transformed fibroblasts of GS01(a homozygote of S283X). SCOT activity of the R268H protein was more vulnerable than the wild-type to heat treatment at 50 degrees C. These results indicated that the R268H mutant protein was clearly more unstable than the wild-type in a temperature-sensitive manner. Furthermore, an analysis of the three-dimensional structure of SCOT showed that the R268H mutation was expected to break a conserved salt bridge between R268 and D52, which would be expected to lead to decreased stability of the protein. Hence we finally concluded that the R268H mutation is a disease-causing one. The stability of mutant protein in transient expression analysis does not always reflect the condition in patients' fibroblasts.