Variations in IBD (ACAD8) in children with elevated C4-carnitine detected by tandem mass spectrometry newborn screening
Variations in IBD (ACAD8) in children with elevated C4-carnitine detected by tandem mass spectrometry newborn screening
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DOI：
10.1203/01.pdr.0000233085.72522.04
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发表时间：
2006-09-01
影响因子：
3.6
通讯作者：
Andresen, Brage S.
中科院分区：
文献类型：
--
作者：
Pedersen, Christina B.;Bischoff, Claus;Andresen, Brage S.
异丁酰辅酶A脱氢酶（IBD）参与缬氨酸的降解。IBD缺乏症于1998年首次报道，随后的遗传学研究确定了酰基辅酶A脱氢酶（ACAD）8（现在的IBD）是导致IBD缺乏症的基因。据报道，只有三个人是IBD基因变异的纯合或复合杂合个体。我们目前在丹麦和美国通过串联质谱（MS/MS）筛查确定的另外四名C-4-肉毒碱升高的新生儿中存在IBD缺陷。三个显示尿排泄的异丁酰甘氨酸，和两个新生儿的成纤维细胞的体外探针分析表明酶IBD缺陷。分子遗传学分析发现了7个新的罕见IBD基因变异（c.348C > A、c.400G > T、c.409G > A、c.455T > C、c.958G > A、c.1000C > T和c.1154G > A）。此外，短链酰基辅酶A脱氢酶（SCAD）基因的序列分析显示，在所有新生儿和首次报道的IBD患者中，流行的c.625G > A易感性变异为杂合性。在分离的线粒体中的功能研究表明，存在于丹麦新生儿中的IBD变异（c.409G > A和c.958G > A）连同先前公布的IBD变异（c.905G > A）干扰蛋白质折叠并降低正确折叠的IBD四聚体的水平。因此，当变体IBD蛋白在Chang细胞中过表达时，可检测到低/无IBD残留酶活性。
The isobutyryl-CoA dehydrogenase (IBD) enzyme is involved in the degradation of valine. IBD deficiency was first reported in 1998 and subsequent genetic investigations identified acyl-CoA dehydrogenase (ACAD) 8, now IBD, as the gene responsible for IBD deficiency. Only three individuals homozygous or compound heterozygous for variations in the IBD gene have been reported. We present IBD deficiency in an additional four newborns with elevated C-4-carnitine identified by tandem mass spectrometry (MS/MS) screening in Denmark and the United States. Three showed urinary excretions of isobutyryl-glycine, and in vitro probe analysis of fibroblasts from two newborns indicated enzymatic IBD defect. Molecular genetic analysis revealed seven new rare variations in the IBD gene (c.348C > A, c.400G > T, c.409G > A, c.455T > C, c.958G > A, c.1000C > T and c.1154G > A). Furthermore, sequence analysis of the short-chain acyl-CoA dehydrogenase (SCAD) gene revealed heterozygosity for the prevalent c.625G > A susceptibility variation in all newborns and in the first reported IBD patient. Functional studies in isolated mitochondria demonstrated that the IBD variations present in the Danish newborn (c.409G > A an c.958G > A) together with a previously published IBD variation (c.905G > A) disturbed protein folding and reduced the levels of correctly folded IBD tetramers. Accordingly, low/no IBD residual enzyme activity was detectable when the variant IBD proteins were overexpressed in Chang cells.