Abstract：
Meier-Gorlin syndrome (MGORS) is an autosomal recessive disorder characterized by short stature, microtia, and patellar hypoplasia, and is caused by pathogenic variants of cellular factors involved in the initiation of DNA replication. We previously reported that biallelic variants in GINS3 leading to amino acid changes at position 24 (p.Asp24) cause MGORS. Here, we describe the phenotype of a new individual homozygous for the Asp24Asn variant. We also report the clinical characteristics of an individual harboring a novel homozygous GINS3 variant (Ile25Phe) and features suggestive of MGORS. Modification of the corresponding residue in yeast Psf3 (Val9Phe) compromised S phase progression compared to a humanized Psf3 Val9Ile variant. Expression of Psf3 Val9Phe in yeast also caused sensitivity to elevated temperature and the replicative stress-inducing drug hydroxyurea, confirming partial loss of function of this variant in vivo and allowing us to upgrade the classification of this variant. Taken together, these data validate the critical importance of the GINS DNA replication complex in the molecular etiology of MGORS.
摘要：
Meier-Gorlin综合征（MGORS）是一种常染色体隐性遗传疾病，以身材矮小为特征，microtia,髌骨发育不全,并且是由参与DNA复制起始的细胞因子的致病变体引起的。我们先前报道了GINS3中的双等位基因变体导致第24位的氨基酸变化（p。Asp24）引起MGORS。这里,我们描述了Asp24Asn变体的新纯合个体的表型。我们还报告了具有新型纯合GINS3变体（Ile25Phe）的个体的临床特征和提示MGORS的特征。与人源化Psf3Val9Ile变体相比,酵母Psf3(Val9Phe)中相应残基的修饰损害了S期进展。Psf3Val9Phe在酵母中的表达也引起了对高温和复制性应激诱导药物羟基脲的敏感性，确认该变体在体内的部分功能丧失，并允许我们升级该变体的分类。一起来看,这些数据证实了GINSDNA复制复合物在MGORS分子病因中的重要意义.
