Department of Human Genetics, Radboud University Medical Center and Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands
Unit for Multidisciplinary Research in Biomedicine, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.
J Med Genet. 2022 Aug;59(8):776-780. doi: 10.1136/jmedgenet-2020-107572. Epub 2021 Aug 5.
Replication of the nuclear genome is an essential step for cell division. Pathogenic variants in genes coding for highly conserved components of the DNA replication machinery cause Meier-Gorlin syndrome (MGORS).
Identification of novel genes associated with MGORS.
Exome sequencing was performed to investigate the genotype of an individual presenting with prenatal and postnatal growth restriction, a craniofacial gestalt of MGORS and coronal craniosynostosis. The analysis of the candidate variants employed bioinformatic tools, structural protein analysis and modelling in budding yeast.
A novel homozygous missense variant NM_016095.2:c.341G>T, p.(Arg114Leu), in was identified. Both non-consanguineous healthy parents carried this variant. Bioinformatic analysis supports its classification as pathogenic. Functional analyses using yeast showed that this variant increases sensitivity to nicotinamide, a compound that interferes with DNA replication processes. The phylogenetically highly conserved residue p.Arg114 localises at the docking site of CDC45 and MCM5 at GINS2. Moreover, the missense change possibly disrupts the effective interaction between the GINS complex and CDC45, which is necessary for the CMG helicase complex (Cdc45/MCM2-7/GINS) to accurately operate. Interestingly, our patient's phenotype is strikingly similar to the phenotype of patients with -related MGORS, particularly those with craniosynostosis, mild short stature and patellar hypoplasia.
is a new disease-associated gene, expanding the genetic aetiology of MGORS.
核基因组的复制是细胞分裂的一个必要步骤。编码 DNA 复制机制高度保守成分的基因中的致病变体导致 Meier-Gorlin 综合征（MGORS）。
鉴定与 MGORS 相关的新基因。
进行外显子组测序，以研究表现为产前和产后生长受限、MGORS 的颅面整体外观和冠状颅缝早闭的个体的基因型。候选变体的分析采用了生物信息学工具、芽殖酵母中的结构蛋白分析和建模。
鉴定出一种新的纯合错义变体 NM_016095.2:c.341G>T，p.(Arg114Leu)，位于 中。非近亲结婚的健康父母均携带此变体。生物信息学分析支持其致病性分类。使用酵母进行的功能分析表明，该变体增加了对烟酰胺的敏感性，烟酰胺是一种干扰 DNA 复制过程的化合物。系统发育高度保守的残基 p.Arg114 位于 CDC45 和 MCM5 在 GINS2 上的对接位点。此外，错义变化可能破坏了 GINS 复合物与 CDC45 之间的有效相互作用，这对于 CMG 解旋酶复合物（Cdc45/MCM2-7/GINS）准确运行是必要的。有趣的是，我们患者的表型与 -相关 MGORS 患者的表型非常相似，特别是那些有颅缝早闭、轻度身材矮小和髌骨发育不良的患者。
是一种新的疾病相关基因，扩展了 MGORS 的遗传病因。
