SDHA mutations causing a multisystem mitochondrial disease: novel mutations and genetic overlap with hereditary tumors.
Defects in complex II of the mitochondrial respiratory chain are a rare cause of mitochondrial disorders. Underlying autosomal-recessive genetic defects are found in most of the 'SDHx' genes encoding complex II (SDHA, SDHB, SDHC, and SDHD) and its assembly factors. Interestingly, SDHx genes also function as tumor suppressor genes in hereditary paragangliomas, pheochromocytomas, and gastrointestinal stromal tumors. In these cases, the affected patients are carrier of a heterozygeous SDHx germline mutation. Until now, mutations in SDHx associated with mitochondrial disease have not been reported in association with hereditary tumors and vice versa. Here, we characterize four patients with isolated complex II deficiency caused by mutations in SDHA presenting with multisystem mitochondrial disease including Leigh syndrome (LS) and/or leukodystrophy. Molecular genetic analysis revealed three novel mutations in SDHA. Two mutations (c.64-2A>G and c.1065-3C>A) affect mRNA splicing and result in loss of protein expression. These are the first mutations described affecting SDHA splicing. For the third new mutation, c.565T>G, we show that it severely affects enzyme activity. Its pathogenicity was confirmed by lentiviral complementation experiments on the fibroblasts of patients carrying this mutation. It is of special interest that one of our LS patients harbored the c.91C>T (p.Arg31*) mutation that was previously only reported in association with paragangliomas and pheochromocytomas, tightening the gap between these two rare disorders. As tumor screening is recommended for SDHx mutation carriers, this should also be considered for patients with mitochondrial disorders and their family members.
1] Nijmegen Center for Mitochondrial Disorders (NCMD) at the Department of Pediatrics, Radboud University Medical Center (Radboudumc), Nijmegen, The Netherlands [2] Centre for Systems Biology and Bioenergetics, Radboudumc, Nijmegen, The Netherlands.
G Herma
GH
Renkema
Nijmegen Center for Mitochondrial Disorders (NCMD) at the Department of Pediatrics, Radboud University Medical Center (Radboudumc), Nijmegen, The Netherlands.
Saskia B
SB
Wortmann
Nijmegen Center for Mitochondrial Disorders (NCMD) at the Department of Pediatrics, Radboud University Medical Center (Radboudumc), Nijmegen, The Netherlands.
Roel J
RJ
Smeets
Centre for Molecular and Biomolecular Informatics, Radboudumc, Nijmegen, The Netherlands.
Hanka
H
Venselaar
1] Nijmegen Center for Mitochondrial Disorders (NCMD) at the Department of Pediatrics, Radboud University Medical Center (Radboudumc), Nijmegen, The Netherlands [2] Centre for Systems Biology and Bioenergetics, Radboudumc, Nijmegen, The Netherlands.
Marion
M
Antoine
Department of Pediatric Gastroenterology and Metabolic Diseases, Wilhelmina Children's Hospital/UMCU, Utrecht, The Netherlands.
Gepke
G
Visser
Section of Clinical and Metabolic Genetics and Department of Pediatrics and Genetic Medicine, Weil-Cornell Medical College, Doha, Qatar.
Tawfeg
T
Ben-Omran
Nijmegen Center for Mitochondrial Disorders (NCMD) at the Department of Pediatrics, Radboud University Medical Center (Radboudumc), Nijmegen, The Netherlands.
Lambert P
LP
van den Heuvel
Department of Medicine, Division of Endocrinology, Radboudumc, Nijmegen, The Netherlands.
Henri J L M
HJ
Timmers
Nijmegen Center for Mitochondrial Disorders (NCMD) at the Department of Pediatrics, Radboud University Medical Center (Radboudumc), Nijmegen, The Netherlands.
Jan A
JA
Smeitink
Nijmegen Center for Mitochondrial Disorders (NCMD) at the Department of Pediatrics, Radboud University Medical Center (Radboudumc), Nijmegen, The Netherlands.
Richard J T
RJ
Rodenburg
D000595:Amino Acid Sequence; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D042963:Electron Transport Complex II / Q000737:chemistry / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007223:Infant; D007888:Leigh Disease / Q000175:diagnosis / Q000235:genetics*; D056784:Leukoencephalopathies / Q000175:diagnosis / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009369:Neoplasms / Q000235:genetics*; D012326:RNA Splicing
D042963:Electron Transport Complex II; C511268:SDHA protein, human