Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
J Med Genet. 2012 Jul;49(7):455-61. doi: 10.1136/jmedgenet-2011-100666. Epub 2012 May 31.
Dyggve--Melchior--Clausen syndrome (DMC) is a chondrodysplasia that bears significant phenotypic resemblance to mucopolysaccharidosis type IV (Morquio disease). Autosomal recessive mutations in DYM are known to cause this disease through its role in Golgi organisation and intracellular traffic, but genetic heterogeneity is suspected.
A family with DMC and normal intellectual development underwent clinical evaluation followed by autozygosity mapping and exome sequencing. Immunoblot and immunofluorescence analyses were performed to characterise the effect of the mutation.
This multiplex consanguineous family links to a novel locus on 4q31.1. Exome sequencing revealed a missense mutation in RAB33B, which encodes a Rab protein with an established role in retrograde Golgi traffic. The mutation qualitatively replaces the invariant lysine residue in the guanine nucleotide-binding domain of this small GTPase protein and leads to marked protein deficiency, making it the likely causative mutation of DMC in this family.
This study identifies a new DMC gene and highlights the role of intracellular traffic in the pathogenesis of this disease.
Dyggve-Melchior-Clausen 综合征（DMC）是一种软骨发育不良症，其表型与黏多糖贮积症 IV 型（Morquio 病）非常相似。DYM 中的常染色体隐性突变通过其在高尔基体组织和细胞内运输中的作用导致这种疾病，但怀疑存在遗传异质性。
一个患有 DMC 且智力发育正常的家系接受了临床评估，随后进行了自交分析和外显子组测序。进行免疫印迹和免疫荧光分析以描述突变的影响。
这个多基因近亲家系与 4q31.1 上的一个新位点相关。外显子组测序发现 RAB33B 中的错义突变，该基因编码一种 Rab 蛋白，在逆行高尔基运输中具有既定作用。该突变定性取代了该小 GTP 酶蛋白鸟嘌呤核苷酸结合域中不变的赖氨酸残基，导致明显的蛋白缺乏，这使其成为该家系中 DMC 的可能致病突变。
本研究确定了一个新的 DMC 基因，并强调了细胞内运输在该疾病发病机制中的作用。
