Farhud Dariush D, Zarif-Yeganeh Marjan, Arian Hajar, Kashi Majid, Rezaee Tayebeh
School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
Department of Basic Sciences, Iranian Academy of Medical Sciences, Tehran, Iran.
Iran J Public Health. 2024 Jun;53(6):1381-1393.
Bone Morphogenetic Proteins and the related Growth and Differentiation Factors (GDFs) are much conserved signaling proteins. GDF5 is pivotal for skeletal development. Several skeletal dysplasia and malformation syndromes are known as a result of mutations in . Multiple Synostosis Syndrome2 (SYNS2) is characterized by tarsal-carpal coalition, humeroradial synostosis, brachydactyly, and proximal symphalangism. In this study, we analyzed a large Iranian pedigree affected with a new type of SYNS2 (Farhud Type) in five successive generations.
In this family-based study (1982-2022), Genetic linkage analysis of the pedigree (58affected, 62healthy) excluded the locus on chromosome 17q21-q22 in our previous study. Thus, we focused on 20q11.22 locus and gene. Genetic investigations were performed on 16 patients with SYNS2 and 40 healthy individuals.
Whole-exome-sequencing results identified a heterozygote missense mutation in exon2 of (NG_008076.1:g.9239G>A, NM_000557.2:c.1424G>A, S475N, rs121909347). This mutation was found in all patients but not in the unaffected individuals. This missense mutation is notable because S475 is strictly conserved among different species, and it is located in a highly conserved and active mature domain of GDF5 (phyloP100way=7.64). The corresponding defect in GDF5 may have unknown interaction with normal active 3 and 4 structure of the product. Further bioinformatics study (amino acid multiple alignments) showed that the S475 is a much-conserved residue in many different species.
These results introduce a new role of in pathogenesis of a SYNS2 (Farhud Type), considered in genetic counseling, prenatal diagnosis, and as a potential target for molecular therapy, if possible.
骨形态发生蛋白及相关的生长分化因子（GDFs）是高度保守的信号蛋白。GDF5对骨骼发育至关重要。已知由于[基因名称]的突变导致了几种骨骼发育异常和畸形综合征。多重性骨连接综合征2（SYNS2）的特征为跗腕骨联合、肱桡关节融合、短指畸形和近端指骨间关节强直。在本研究中，我们分析了一个连续五代受新型SYNS2（法尔胡德型）影响的大型伊朗家系。
在这项基于家系的研究（1982 - 2022年）中，家系（58名患者，62名健康者）的遗传连锁分析在我们之前的研究中排除了17号染色体q21 - q22位点。因此，我们聚焦于20q11.22位点和[基因名称]基因。对16例SYNS2患者和40名健康个体进行了基因研究。
全外显子测序结果在[基因名称]（NG_008076.1:g.9239G>A，NM_000557.2:c.1424G>A，S475N，rs121909347）的外显子2中鉴定出一个杂合错义突变。该突变在所有患者中均被发现，而在未受影响的个体中未发现。这个错义突变值得注意，因为S475在不同物种中严格保守，且它位于GDF5的一个高度保守且活跃的成熟结构域中（phyloP100way = 7.64）。GDF5中的相应缺陷可能与产物正常的活性3和4结构存在未知的相互作用。进一步的生物信息学研究（氨基酸多序列比对）表明，S475在许多不同物种中是一个高度保守的残基。
这些结果揭示了[基因名称]在一种SYNS2（法尔胡德型）发病机制中的新作用，在遗传咨询、产前诊断中应予以考虑，并且如果可能的话，可作为分子治疗的潜在靶点。
