Institute of Biomedical and Genetic Engineering, 24-Mauve area, G-9/1, Islamabad 44000, Pakistan.
Department of Molecular Biology and Genetics, Institute of Basic Medical Science, Faculty of Basic Medical Sciences, Khyber Medical University, Phase V Hayatabad, Peshawar 25000, Pakistan.
Medicina (Kaunas). 2022 Dec 31;59(1):100. doi: 10.3390/medicina59010100.
: Hereditary multiple exostoses (HME) is a disease characterized by cartilage-capped bony protuberances at the site of growth plates of long bones. Functional mutations in the exostosin genes ( and ) are reported to affect the hedgehog signalling pathways leading to multiple enchondromatosis. However, the exact role of each EXT protein in the regulation of heparan sulphate (HS) chain elongation is still an enigma. In this study, a Pakistani family with HME is investigated to find out the genetic basis of the disease. : Genotyping of eight members of the family by amplifying microsatellite markers, tightly linked to the and genes. : The study revealed linkage of the HME family to the locus 8q24.1. Sanger sequencing identified a heterozygous deletion () in exon 1 of , segregating with the disease phenotype in the family. In silico analysis predicted a shift in the frame causing an early stop codon (p.R83GfsX52). The predicted dwarf protein constituting 134 amino acids was functionally aberrant with a complete loss of the catalytic domain at the C-terminus. Interestingly, an alternative open reading frame 3 (ORF3) caused by the frame shift is predicted to encode a protein sequence, identical to the wild type and containing the catalytic domain, but lacking the first 100 amino acids of the wild-type EXT1 protein. : Consequently, haploinsufficiency could be the cause of HME in the investigated family as the mutated copy of is ineffective for complex formation. The predicted ORF3 protein could be of great significance in understanding several aspects of HME pathogenesis.
遗传性多发性外生骨疣（HME）是一种以长骨生长板部位软骨帽状骨突起为特征的疾病。据报道，外生骨素基因（和）的功能突变会影响 hedgehog 信号通路，导致多发性内生骨软骨瘤。然而，每个 EXT 蛋白在调节肝素硫酸（HS）链延伸中的确切作用仍然是一个谜。在这项研究中，对一个患有 HME 的巴基斯坦家族进行了调查，以找出该疾病的遗传基础。
通过扩增与和基因紧密连锁的微卫星标记对该家族的 8 名成员进行基因分型。
研究揭示了 HME 家族与 8q24.1 上的位点连锁。Sanger 测序在 基因的外显子 1 中发现了一个杂合缺失（），与家族中的疾病表型相分离。计算机分析预测移码导致提前出现终止密码子（p.R83GfsX52）。预测的 dwarf 蛋白由 134 个氨基酸组成，功能异常，C 末端的催化结构域完全缺失。有趣的是，由移码引起的替代开放阅读框 3（ORF3）预计会编码一个与野生型相同的蛋白序列，并包含催化结构域，但缺乏野生型 EXT1 蛋白的前 100 个氨基酸。
在所研究的家族中，杂合不足可能是 HME 的原因，因为突变的拷贝不能有效地形成 EXT1 复合物。预测的 ORF3 蛋白对于理解 HME 发病机制的几个方面可能具有重要意义。
