Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency.
Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency.
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DOI：
10.1136/jmedgenet-2012-101146
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发表时间：
2012-09
影响因子：
4
通讯作者：
Taylor RW
中科院分区：
文献类型：
--
作者：
Alston CL;Davison JE;Meloni F;van der Westhuizen FH;He L;Hornig-Do HT;Peet AC;Gissen P;Goffrini P;Ferrero I;Wassmer E;McFarland R;Taylor RW
孤立性复合物II缺乏症是一种罕见的线粒体疾病，约占所有呼吸链缺乏症诊断的2%。琥珀酸脱氢酶（SDH）基因（SDHA、SDHB、SDHC和SDHD）是常染色体编码的，并通过两种已知的组装因子（SDHAF 1和SDHAF 2）的作用转录复合物II的缀合异源四聚体。只有少数报告描述遗传性SDH基因缺陷是儿科线粒体疾病的原因，涉及SDHA（Leigh综合征，心肌病）或SDHAF 1（婴儿白质脑病）。然而，所有四个SDH基因，连同SDHAF 2，具有已知的肿瘤抑制功能，与许多生殖细胞和体细胞突变报告与遗传性癌症综合征，包括副神经节瘤和嗜铬细胞瘤。在这里，我们报告的临床和分子研究的两个病人的组织化学和生化证据的严重，孤立的复合物II缺乏症，由于新的SDH基因突变;第一位患者由于复合杂合p.Thr508Ile和p.Ser509Leu SDHA突变而表现出心肌病和脑白质营养不良，而第二名患者表现为张力减退和脑白质营养不良，MR波谱显示脑琥珀酸升高，这是由于新的纯合p.Asp48ValSDHB突变所致。Western印迹和BN-PAGE研究证实了相关SDH亚基的稳态水平降低和复合物II组装受损。来自酵母互补研究的证据为SDHB突变的致病性提供了额外的支持。我们的报告代表了SDHB突变作为遗传性线粒体呼吸链疾病的原因的第一个例子，并扩展了孤立的复合物II缺乏症患者的SDHA突变谱。
Isolated complex II deficiency is a rare form of mitochondrial disease, accounting for approximately 2% of all respiratory chain deficiency diagnoses. The succinate dehydrogenase (SDH) genes (SDHA, SDHB, SDHC and SDHD) are autosomally-encoded and transcribe the conjugated heterotetramers of complex II via the action of two known assembly factors (SDHAF1 and SDHAF2). Only a handful of reports describe inherited SDH gene defects as a cause of paediatric mitochondrial disease, involving either SDHA (Leigh syndrome, cardiomyopathy) or SDHAF1 (infantile leukoencephalopathy). However, all four SDH genes, together with SDHAF2, have known tumour suppressor functions, with numerous germline and somatic mutations reported in association with hereditary cancer syndromes, including paraganglioma and pheochromocytoma. Here, we report the clinical and molecular investigations of two patients with histochemical and biochemical evidence of a severe, isolated complex II deficiency due to novel SDH gene mutations; the first patient presented with cardiomyopathy and leukodystrophy due to compound heterozygous p.Thr508Ile and p.Ser509Leu SDHA mutations, while the second patient presented with hypotonia and leukodystrophy with elevated brain succinate demonstrated by MR spectroscopy due to a novel, homozygous p.Asp48Val SDHB mutation. Western blotting and BN-PAGE studies confirmed decreased steady-state levels of the relevant SDH subunits and impairment of complex II assembly. Evidence from yeast complementation studies provided additional support for pathogenicity of the SDHB mutation. Our report represents the first example of SDHB mutation as a cause of inherited mitochondrial respiratory chain disease and extends the SDHA mutation spectrum in patients with isolated complex II deficiency.
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影响因子：
30.8
作者：
BOURGERON, T;RUSTIN, P;ROTIG, A
通讯作者：
ROTIG, A
影响因子：
51.1
作者：
Bayley, Jean-Pierre;Kunst, Henricus P. M.;Robledo, Mercedes
通讯作者：
Robledo, Mercedes
影响因子：
4.8
作者：
Baruffini, Enrico;Ferrero, Iliana;Foury, Francoise
通讯作者：
Foury, Francoise
影响因子：
1.7
作者：
Bugiani, Marianna;Lamantea, Eleonora;Uziel, Graziella
通讯作者：
Uziel, Graziella
影响因子：
9.8
作者：
Astuti, D;Latif, F;Maher, ER
通讯作者：
Maher, ER