SDHA mutations causing a multisystem mitochondrial disease: novel mutations and genetic overlap with hereditary tumors

Abstract

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.64-2A4G and c.1065-3C4A) 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.565T4G, 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.91C4T (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.

Leukoencephalopathy due to Complex II Deficiency and Bi-Allelic SDHB Mutations: Further Cases and Implications for Genetic Counselling

“…The p. Asp48Val variant has been found in six out of seven reported patients with complex II deficiency due to SDHB mutations (Alston et al 2012;Helman et al 2015), whereas the p.Arg230His variant has been reported in heterozygous form in patients with familial paraganglioma/pheochromocytoma (Amar et al 2005) and/or renal cell cancer (Ricketts et al 2012). To our knowledge, this is only the second example in the literature where one specific SDHx mutation is associated with both recessive mitochondrial disease in one patient and familial paraganglioma/pheochromocytoma in others; previously, this has exclusively been described for the c.91C>T (p.Arg31*) variant in SDHA (Renkema et al 2015). Clinically, the phenotypic presentation of both SDHB patients in this report lies well within the phenotypic spectrum of complex II deficiency (Jain-Ghai et al 2013) as well as of SDHB deficiency (Alston et al 2012;Helman et al 2015).…”

“…Also with these lower estimates, the need for expanded family testing and referral of heterozygous mutation carriers to a surveillance program remains unchanged. This should also be considered in the families of patients with bi-allelic mutations in SDHD and SDHA that also have been described with a dual role, with mitochondrial disease in patients with bi-allelic mutations and risk of paraganglioma/pheochromocytoma and cancer in heterozygotes (Ricketts et al 2010;Kunst et al 2011;Welander et al 2011;Renkema et al 2015).…”

Interaction of germline variants in a family with a history of early‐onset clear cell renal cell carcinoma

“…SDH genes, commonly collectively referred as SDHx , function as tumor suppressor genes in hereditary paragangliomas, pheochromocytomas, and gastrointestinal stromal tumors (GISTs) (Renkema, et al, ). SDH‐deficient renal carcinomas were first identified in 2004 (Vanharanta, et al, ) and accepted as a unique subtype of renal tumor in 2016 (Moch, Cubilla, Humphrey, Reuter, & Ulbright, ).…”

“…After flavination (addition of FAD) of mature SDHA, mediated by SDHAF2, SDHAF4 binds to SDHA to reduce autooxidation. SDHAF3 facilitates the formation of an SDHA-SDHB complex that assembles with SDHC and SDHD located in the inner membrane (Renkema, et al, 2015). SDH-deficient renal carcinomas were first identified in 2004 (Vanharanta, et al, 2004) and accepted as a unique subtype of renal tumor in 2016 (Moch, Cubilla, Humphrey, Reuter, & Ulbright, 2016).…”

Single nucleotide mtDNA polymorphisms may contribute to cancerogenesis in mitochondrial disorders

“…These include the succinate dehydrogenase genes SDHA, SDHB, SDHC, and SDHD, and the iso-citrate dehydrogenase genes IDH1 and IDH2 [van Gisbergen et al, 2015]. Particularly, mutations in SDHA are associated with hereditary paragangliomas, pheochromocytomas, or gastrointestinal stroma tumors [Bayley et al, 2005;Renkema et al, 2015]. IDH1 and IDH2 mutations are frequently associated with gliomas.…”