CSGALNACT1-congenital disorder of glycosylation: A mild skeletal dysplasia with advanced bone age.
CSGALNACT1-congenital disorder of glycosylation: A mild skeletal dysplasia with advanced bone age.
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CSGALNACT1-先天性糖基化障碍：骨龄较高的轻度骨骼发育不良。
DOI：
10.1002/humu.23952
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发表时间：
2020
期刊：
影响因子：
3.9
通讯作者：
Vodopiutz,
中科院分区：
文献类型：
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作者：
Mizumoto,Shuji;Janecke,AndreasR;Sadeghpour,Azita;Povysil,Gundula;McDonald,MarieT;Unger,Sheila;Greber-Platzer,Susanne;Deak,KristenL;Katsanis,Nicholas;Superti-Furga,Andrea;Sugahara,Kazuyuki;Davis,EricaE;Yamada,Shuhei;Vodopiutz,
先天性糖基化障碍（CDG）包括大量影响聚糖生物合成和附着的遗传代谢缺陷。CDG表现为广泛的疾病，最常见的包括神经发育和骨骼异常以及皮肤松弛。先前已经描述了2例双等位基因CSGALNACT 1变异和轻度骨骼发育不良的患者。我们研究了两名不相关的患者，他们表现为身材矮小，骨龄晚期，面部畸形和轻度语言发育迟缓，其中三外显子组测序鉴定出新的双等位基因CSGALNACT 1变体：一名患者为c.1294G>T（p.Asp432Tyr）的复合杂合性和外显子4（包括起始密码子）的缺失，另一名患者为c.791A>G（p.Asn264Ser）的纯合性。CSGALNACT 1编码CSGalNAcT-1，这是硫酸化糖胺聚糖软骨素和硫酸皮肤素生物合成中的关键酶。生物化学研究表明，新型错义变体的CSGalNAcT-1活性显著降低，如先前针对p.Pro384Arg变体所报道的。与对照组相比，在患者的成纤维细胞中观察到软骨素、皮肤素和硫酸乙酰肝素部分的水平改变。我们的数据表明，CSGALNACT 1中的双等位基因功能丧失突变会干扰糖胺聚糖合成，并导致骨龄提前的轻度骨骼发育不良，CSGALNACT 1-CDG。
Congenital disorders of glycosylation (CDGs) comprise a large number of inherited metabolic defects that affect the biosynthesis and attachment of glycans. CDGs manifest as a broad spectrum of disease, most often including neurodevelopmental and skeletal abnormalities and skin laxity. Two patients with biallelicCSGALNACT1variants and a mild skeletal dysplasia have been described previously. We investigated two unrelated patients presenting with short stature with advanced bone age, facial dysmorphism, and mild language delay, in whom trio‐exome sequencing identified novel biallelicCSGALNACT1variants: compound heterozygosity for c.1294G>T (p.Asp432Tyr) and the deletion of exon 4 that includes the start codon in one patient, and homozygosity for c.791A>G (p.Asn264Ser) in the other patient. CSGALNACT1encodes CSGalNAcT‐1, a key enzyme in the biosynthesis of sulfated glycosaminoglycans chondroitin and dermatan sulfate. Biochemical studies demonstrated significantly reduced CSGalNAcT‐1 activity of the novel missense variants, as reported previously for the p.Pro384Arg variant. Altered levels of chondroitin, dermatan, and heparan sulfate moieties were observed in patients’ fibroblasts compared to controls. Our data indicate that biallelic loss‐of‐function mutations inCSGALNACT1disturb glycosaminoglycan synthesis and cause a mild skeletal dysplasia with advanced bone age, CSGALNACT1‐CDG.