Imagine Institute, Laboratory of Inherited Kidney Diseases, Institut National de la Santé et de la Recherche Médicale (INSERM) Unités Mixtes de Recherche (UMR) 1163, Université Paris Cité, Paris, France.
School of Biological Sciences, University of the Punjab, Lahore, Pakistan.
J Bone Miner Res. 2022 Sep;37(9):1642-1652. doi: 10.1002/jbmr.4639. Epub 2022 Jul 19.
Skeletal dysplasias comprise a large spectrum of mostly monogenic disorders affecting bone growth, patterning, and homeostasis, and ranging in severity from lethal to mild phenotypes. This study aimed to underpin the genetic cause of skeletal dysplasia in three unrelated families with variable skeletal manifestations. The six affected individuals from three families had severe short stature with extreme shortening of forelimbs, short long-bones, and metatarsals, and brachydactyly (family 1); mild short stature, platyspondyly, and metaphyseal irregularities (family 2); or a prenatally lethal skeletal dysplasia with kidney features suggestive of a ciliopathy (family 3). Genetic studies by whole genome, whole exome, and ciliome panel sequencing identified in all affected individuals biallelic missense variants in KIF24, which encodes a kinesin family member controlling ciliogenesis. In families 1 and 3, with the more severe phenotype, the affected subjects harbored homozygous variants (c.1457A>G; p.(Ile486Val) and c.1565A>G; p.(Asn522Ser), respectively) in the motor domain which plays a crucial role in KIF24 function. In family 2, compound heterozygous variants (c.1697C>T; p.(Ser566Phe)/c.1811C>T; p.(Thr604Met)) were found C-terminal to the motor domain, in agreement with a genotype-phenotype correlation. In vitro experiments performed on amnioblasts of one affected fetus from family 3 showed that primary cilia assembly was severely impaired, and that cytokinesis was also affected. In conclusion, our study describes novel forms of skeletal dysplasia associated with biallelic variants in KIF24. To our knowledge this is the first report implicating KIF24 variants as the cause of a skeletal dysplasia, thereby extending the genetic heterogeneity and the phenotypic spectrum of rare bone disorders and underscoring the wide range of monogenetic skeletal ciliopathies. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
骨骼发育不良包括一大类主要由单基因疾病引起的疾病，这些疾病影响骨骼的生长、模式和内稳态，严重程度从致死性到轻度表型不等。本研究旨在为三个具有不同骨骼表现的无关家族的骨骼发育不良的遗传原因提供依据。三个家族的六个受影响个体具有严重的身材矮小，四肢极度缩短，长骨和跖骨短小，短指畸形（家族 1）；轻度身材矮小，脊柱融合，干骺端不规则（家族 2）；或产前致死性骨骼发育不良，肾脏特征提示纤毛病（家族 3）。通过全基因组、全外显子组和纤毛组测序进行的遗传研究，在所有受影响个体中发现了编码控制纤毛发生的驱动蛋白家族成员 KIF24 的双等位基因突变。在表型更严重的家族 1 和 3 中，受影响的个体携带位于运动结构域的纯合变异（c.1457A>G;p.(Ile486Val)和 c.1565A>G;p.(Asn522Ser)），该结构域在 KIF24 功能中起着关键作用。在家族 2 中，发现了运动结构域下游的复合杂合变异（c.1697C>T;p.(Ser566Phe)/c.1811C>T;p.(Thr604Met)），与基因型-表型相关性一致。在来自家族 3 的一个受影响胎儿的羊水细胞中进行的体外实验表明，初级纤毛组装严重受损，细胞分裂也受到影响。总之，本研究描述了与 KIF24 双等位基因突变相关的新形式的骨骼发育不良。据我们所知，这是首次报道 KIF24 变异是骨骼发育不良的原因，从而扩展了罕见骨骼疾病的遗传异质性和表型谱，并强调了广泛的单基因骨骼纤毛病。© 2022 作者。骨骼与矿物研究杂志由 Wiley 期刊出版公司代表美国骨骼与矿物研究协会（ASBMR）出版。
