Bi-allelic Mutations in NADSYN1 Cause Multiple Organ Defects and Expand the Genotypic Spectrum of Congenital NAD Deficiency Disorders
Publication in refereed journal


摘要Birth defects occur in up to 3% of all live births and are the leading cause of infant death. Here we present five individuals from four unrelated families, individuals who share similar phenotypes with disease-causal bi-allelic variants in NADSYN1, encoding NAD synthetase 1, the final enzyme of the nicotinamide adenine dinucleotide (NAD) de novo synthesis pathway. Defects range from the isolated absence of both kidneys to multiple malformations of the vertebrae, heart, limbs, and kidney, and no affected individual survived for more than three months postnatally. NAD is an essential coenzyme for numerous cellular processes. Bi-allelic loss-of-function mutations in genes required for the de novo synthesis of NAD were previously identified in individuals with multiple congenital abnormalities affecting the heart, kidney, vertebrae, and limbs. Functional assessments of NADSYN1 missense variants, through a combination of yeast complementation and enzymatic assays, show impaired enzymatic activity and severely reduced NAD levels. Thus, NADSYN1 represents an additional gene required for NAD synthesis during embryogenesis, and NADSYN1 has bi-allelic missense variants that cause NAD deficiency-dependent malformations. Our findings expand the genotypic spectrum of congenital NAD deficiency disorders and further implicate mutation of additional genes involved in de novo NAD synthesis as potential causes of complex birth defects.
著者Szot Justin O., Campagnolo Carla, Cao Ye, Iyer Kavitha R., Cuny Hartmut, Drysdale Thomas, Flores-Daboub Josue A., Bi Weimin, Westerfield Lauren, Liu Pengfei, Leung Tse Ngong, Choy Kwong Wai, Chapman Gavin, Xiao Rui, Siu VictoriaM., Dunwoodie Sally L.
期刊名稱American Journal of Human Genetics
頁次129 - 136
關鍵詞Congenital NAD Deficiency Disorder, NADSYN1, autosomal recessive, kynurenine pathway, NAD, NAD synthesis, VACTERL

上次更新時間 2020-13-07 於 23:50