Pedersen Christina B, Bischoff Claus, Christensen Ernst, Simonsen Henrik, Lund Allan M, Young Sarah P, Koeberl Dwight D, Millington David S, Roe Charles R, Roe Diane S, Wanders Ronald J A, Ruiter Jos P N, Keppen Laura D, Stein Quinn, Knudsen Inga, Gregersen Niels, Andresen Brage S
Research Unit for Molecular Medicine, Aarhus University Hospital, Skejby Sygehus, 8200 Aarhus N, Denmark.
Pediatr Res. 2006 Sep;60(3):315-20. doi: 10.1203/01.pdr.0000233085.72522.04. Epub 2006 Jul 20.
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 and 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.
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，随后的基因研究确定酰基辅酶A脱氢酶（ACAD）8（现称为IBD）是导致IBD缺乏症的基因。据报道，只有三名IBD基因变异的纯合子或复合杂合子个体。我们报告了另外四名新生儿的IBD缺乏症，这些新生儿通过丹麦和美国的串联质谱（MS/MS）筛查发现C(4)-肉碱水平升高。三名患儿尿中出现异丁酰甘氨酸，对两名新生儿的成纤维细胞进行的体外探针分析表明存在酶促IBD缺陷。分子遗传学分析揭示了IBD基因中的七个新的罕见变异（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，所有新生儿以及首例报道的IBD患者中均存在常见的c.625G>A易感性变异的杂合性。在分离的线粒体中进行的功能研究表明，丹麦新生儿中存在的IBD变异（c.409G>A和c.958G>A）与先前发表的IBD变异（c.905G>A）共同干扰了蛋白质折叠，并降低了正确折叠的IBD四聚体水平。因此，当变异的IBD蛋白在Chang细胞中过表达时，可检测到低/无IBD残余酶活性。
