Novel mutations in the mitochondrial complex I assembly gene NDUFAF5 reveal heterogeneous phenotypes.
Novel mutations in the mitochondrial complex I assembly gene NDUFAF5 reveal heterogeneous phenotypes.
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DOI：
10.1016/j.ymgme.2018.11.001
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发表时间：
2019-01
影响因子：
3.8
通讯作者：
Abdenur JE
中科院分区：
文献类型：
--
作者：
Simon MT;Eftekharian SS;Stover AE;Osborne AF;Braffman BH;Chang RC;Wang RY;Steenari MR;Tang S;Hwu PW;Taft RJ;Benke PJ;Abdenur JE
Primary mitochondrial complex I deficiency is the most common defect of the mitochondrial respiratory chain. It is caused by defects in structural components and assembly factors of this large protein complex. Mutations in the assembly factor NDUFAF5 are rare, with only five families reported to date. This study provides clinical, biochemical, molecular and functional data for four unrelated additional families, and three novel pathogenic variants. Three cases presented in infancy with lactic acidosis and classic Leigh syndrome. One patient, however, has a milder phenotype, with symptoms starting at 27 months and a protracted clinical course with improvement and relapsing episodes. She is homozygous for a previously reported mutation, p.Met279Arg and alive at 19 years with mild neurological involvement, normal lactate but abnormal urine organic acids. We found the same mutation in one of our severely affected patients in compound heterozygosity with a novel p.Lys52Thr mutation. Both patients with p.Met279Arg are of Taiwanese descent and had severe hyponatremia. Our third and fourth patients, both Caucasian, shared a common, newly described, missense mutation p.Lys109Asn which we show induces skipping of exon 3. Both Caucasian patients were compound heterozygotes, one with a previously reported Ashkenazi founder mutation while the other was negative for additional exonic variants. Whole genome sequencing followed by RNA studies revealed a novel deep intronic variant at position c.223-907A>C inducing an exonic splice enhancer. Our report adds significant new information to the mutational spectrum of NDUFAF5, further delineating the phenotypic heterogeneity of this mitochondrial defect.
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DOI：
10.1038/gim.2017.119
发表时间：
2018-04
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Lionel AC;Costain G;Monfared N;Walker S;Reuter MS;Hosseini SM;Thiruvahindrapuram B;Merico D;Jobling R;Nalpathamkalam T;Pellecchia G;Sung WWL;Wang Z;Bikangaga P;Boelman C;Carter MT;Cordeiro D;Cytrynbaum C;Dell SD;Dhir P;Dowling JJ;Heon E;Hewson S;Hiraki L;Inbar-Feigenberg M;Klatt R;Kronick J;Laxer RM;Licht C;MacDonald H;Mercimek-Andrews S;Mendoza-Londono R;Piscione T;Schneider R;Schulze A;Silverman E;Siriwardena K;Snead OC;Sondheimer N;Sutherland J;Vincent A;Wasserman JD;Weksberg R;Shuman C;Carew C;Szego MJ;Hayeems RZ;Basran R;Stavropoulos DJ;Ray PN;Bowdin S;Meyn MS;Cohn RD;Scherer SW;Marshall CR
通讯作者：
Marshall CR
影响因子：
14.9
作者：
Desmet FO;Hamroun D;Lalande M;Collod-Béroud G;Claustres M;Béroud C
通讯作者：
Béroud C
影响因子：
1.4
作者：
Lohmeier, K.;Distelmaier, F.;Hoehn, T.
通讯作者：
Hoehn, T.
影响因子：
9.8
作者：
Sugiana, Canny;Pagliarini, David J.;Thorburn, David R.
通讯作者：
Thorburn, David R.
影响因子：
29
作者：
Guerrero-Castillo, Sergio;Baertling, Fabian;Nijtmans, Leo
通讯作者：
Nijtmans, Leo