School of Biological Sciences, University of the Punjab, Lahore, Pakistan.
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
J Med Genet. 2021 May;58(5):351-356. doi: 10.1136/jmedgenet-2020-106929. Epub 2020 Jun 26.
Studies exploring molecular mechanisms underlying congenital skeletal disorders have revealed novel regulators of skeletal homeostasis and shown protein glycosylation to play an important role.
To identify the genetic cause of rhizomelic skeletal dysplasia in a consanguineous Pakistani family.
Clinical investigations were carried out for four affected individuals in the recruited family. Whole genome sequencing (WGS) was completed using DNA from two affected and two unaffected individuals from the family. Sequencing data were processed, filtered and analysed. In silico analyses were performed to predict the effects of the candidate variant on the protein structure and function. Small interfering RNAs (siRNAs) were used to study the effect of gene knockdown in primary rat chondrocytes.
The patients presented with short stature due to extreme shortening of the proximal segments of the limbs. Radiographs of one individual showed hip dysplasia and severe platyspondyly. WGS data analyses identified a homozygous missense variant c.226G>A; p.(Glu76Lys) in , segregating with the disease. Glucosamine 6-phosphate N-acetyltransferase, encoded by the highly conserved gene , is one of the enzymes required for synthesis of uridine diphosphate N-acetylglucosamine, which participates in protein glycosylation. Knockdown of by siRNAs decreased cellular proliferation and expression of chondrocyte differentiation markers collagen type 2 and alkaline phosphatase, indicating that is important for growth plate chondrocyte proliferation and differentiation.
This study describes a novel severe skeletal dysplasia associated with a biallelic, variant in . Our data suggest that GNPNAT1 is important for growth plate chondrogenesis.
探索先天性骨骼疾病相关分子机制的研究揭示了骨骼动态平衡的新调节因子，并表明蛋白质糖基化起着重要作用。
鉴定一个巴基斯坦近亲家族中多发性骨软骨发育不良的遗传原因。
对所招募家庭中的 4 名受影响个体进行临床研究。对来自该家庭的 2 名受影响个体和 2 名未受影响个体的 DNA 进行全基因组测序（WGS）。对测序数据进行处理、过滤和分析。通过计算机分析预测候选变异对蛋白质结构和功能的影响。使用小干扰 RNA（siRNA）研究基因敲低对原代大鼠软骨细胞的影响。
患者因四肢近端极度缩短而身材矮小。一名患者的 X 光片显示髋关节发育不良和严重的扁平椎骨。WGS 数据分析确定了一个纯合错义变异 c.226G>A；p.（Glu76Lys）在 中，与疾病共分离。由高度保守基因 编码的葡萄糖胺 6-磷酸 N-乙酰转移酶是合成尿苷二磷酸 N-乙酰葡萄糖胺所需的酶之一，该酶参与蛋白质糖基化。siRNA 敲低 降低了细胞增殖和软骨细胞分化标志物胶原 2 型和碱性磷酸酶的表达，表明 对于生长板软骨细胞的增殖和分化很重要。
本研究描述了一种与双等位基因 相关的新型严重骨骼发育不良。我们的数据表明 GNPNAT1 对于生长板软骨发生很重要。
