Loeffen J, Smeitink J, Triepels R, Smeets R, Schuelke M, Sengers R, Trijbels F, Hamel B, Mullaart R, van den Heuvel L
Department of Pediatrics, Nijmegen Center for Mitochondrial Disorders, The Netherlands.
Am J Hum Genet. 1998 Dec;63(6):1598-608. doi: 10.1086/302154.
Nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase (complex I) is the largest multiprotein enzyme complex of the respiratory chain. The nuclear-encoded NDUFS8 (TYKY) subunit of complex I is highly conserved among eukaryotes and prokaryotes and contains two 4Fe4S ferredoxin consensus patterns, which have long been thought to provide the binding site for the iron-sulfur cluster N-2. The NDUFS8 cDNA contains an open reading frame of 633 bp, coding for 210 amino acids. Cycle sequencing of amplified NDUFS8 cDNA of 20 patients with isolated enzymatic complex I deficiency revealed two compound heterozygous transitions in a patient with neuropathologically proven Leigh syndrome. The first mutation was a C236T (P79L), and the second mutation was a G305A (R102H). Both mutations were absent in 70 control alleles and cosegregated within the family. A progressive clinical phenotype proceeding to death in the first months of life was expressed in the patient. In the 19 other patients with enzymatic complex I deficiency, no mutations were found in the NDUFS8 cDNA. This article describes the first molecular genetic link between a nuclear-encoded subunit of complex I and Leigh syndrome.
烟酰胺腺嘌呤二核苷酸（NADH）：泛醌氧化还原酶（复合体I）是呼吸链中最大的多蛋白酶复合体。复合体I的核编码亚基NDUFS8（TYKY）在真核生物和原核生物中高度保守，包含两个4Fe4S铁氧化还原蛋白共有模式，长期以来人们一直认为这两个模式为铁硫簇N-2提供结合位点。NDUFS8 cDNA包含一个633 bp的开放阅读框，编码210个氨基酸。对20例孤立性酶复合体I缺乏症患者的扩增NDUFS8 cDNA进行循环测序，发现在一例经神经病理学证实为Leigh综合征的患者中存在两个复合杂合性转变。第一个突变是C236T（P79L），第二个突变是G305A（R102H）。这两个突变在70个对照等位基因中均未出现，且在家族中共同分离。该患者表现出在生命最初几个月内逐渐发展至死亡的临床表型。在其他19例酶复合体I缺乏症患者中，未在NDUFS8 cDNA中发现突变。本文描述了复合体I的一个核编码亚基与Leigh综合征之间的首个分子遗传学联系。
