A novel SMARCAL1 missense mutation that affects splicing in a severely affected Schimke immunoosseous dysplasia patient

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• 作者：Jimena Barraza-Garcí ; a^a ; ^b ; ^c ; Carlos I. Rivera-Pedroza^a ; ^c ; Alberta Belinchó ; n^a ; ^b ; ^c ; Carlota Fern&aacute ; ndez-Camblor^d ; Blanca Valenciano-Fuente^e ; Pablo Lapunzina^a ; ^b ; ^c ; Karen E. Heath^a ; ^b ; ^c ; ^{karen.heath@salud.madrid.org" class="auth_mail" title="E-mail the corresponding author}
• 关键词：SMARCAL1 ; SIOD ; Skeletal dysplasia ; Nephropathy ; Immunodeficiency
• 刊名：European Journal of Medical Genetics
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：59
• 期：8
• 页码：363-366
• 全文大小：583 K

文摘

Schimke immunoosseous dysplasia (SIOD) is an autosomal recessive disease characterized by skeletal dysplasia, focal segmental glomerulosclerosis, renal failure and immunodeficiency. In this work, we report the molecular studies undertaken in a severely affected SIOD patient that died at six years old due to nephropathy. The patient was screened for mutations using a targeted skeletal dysplasias panel. A homozygous novel missense mutation was identified, c.1615C > G (p.[Leu539Val]) that was predicted as mildly pathogenic by in silico pathogenicity prediction tools. However, splicing prediction software suggested that this variant may create a new splicing donor site in exon 9, which was subsequently confirmed using a minigene assay in HEK293 cells. Thus, the splicing alteration, c.1615C > G; r.1615c > g, 1615_1644del; (p.[Leu539_Ile548del]), results in the loss of 10 amino acids of the HARP-ATPase catalytic domain and the RPA-binding domain. Several studies have demonstrated a weak genotype-phenotype correlation among such patients. Thus, the molecular characterization has helped us to understand why a predicted weakly pathogenic missense mutation results in severe SIOD and should be considered in similar scenarios.