De novo heterozygous variants in KIF5B cause kyphomelic dysplasia.
KIF5B
de novo variant
kyphomelic dysplasia
skeletal dysplasia
Journal
Clinical genetics
ISSN: 1399-0004
Titre abrégé: Clin Genet
Pays: Denmark
ID NLM: 0253664
Informations de publication
Date de publication:
07 2022
07 2022
Historique:
revised:
23
03
2022
received:
07
02
2022
accepted:
24
03
2022
pubmed:
29
3
2022
medline:
16
6
2022
entrez:
28
3
2022
Statut:
ppublish
Résumé
Kyphomelic dysplasia is a heterogeneous group of skeletal dysplasias characterized by severe bowing of the limbs associated with other variable findings, such as narrow thorax and abnormal facies. We searched for the genetic etiology of this disorder. Four individuals diagnosed with kyphomelic dysplasia were enrolled. We performed whole-exome sequencing and evaluated the pathogenicity of the identified variants. All individuals had de novo heterozygous variants in KIF5B encoding kinesin-1 heavy chain: two with c.272A>G:p.(Lys91Arg), one with c.584C>A:p.(Thr195Lys), and the other with c.701G>T:p.(Gly234Val). All variants involved conserved amino acids in or close to the ATPase activity-related motifs in the catalytic motor domain of the KIF5B protein. All individuals had sharp angulation of the femora and humeri, distinctive facial features, and neonatal respiratory distress. Short stature was observed in three individuals. Three developed postnatal osteoporosis with subsequent fractures, two showed brachycephaly, and two were diagnosed with optic atrophy. Our findings suggest that heterozygous KIF5B deleterious variants cause a specific form of kyphomelic dysplasia. Furthermore, alterations in kinesins cause various symptoms known as kinesinopathies, and our findings also extend the phenotypic spectrum of kinesinopathies.
Substances chimiques
KIF5B protein, human
0
Kinesins
EC 3.6.4.4
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
3-11Informations de copyright
© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Références
Mortier GR, Cohn DH, Cormier-Daire V, et al. Nosology and classification of genetic skeletal disorders: 2019 revision. Am J Med Genet A. 2019;179(12):2393-2419.
Hirokawa N, Noda Y. Intracellular transport and kinesin superfamily proteins, KIFs: structure, function, and dynamics. Physiol Rev. 2008;88(3):1089-1118.
Kalantari S, Filges I. 'Kinesinopathies': emerging role of the kinesin family member genes in birth defects. J Med Genet. 2020;57(12):797-807.
Novas R, Cardenas-Rodriguez M, Lepanto P, et al. Kinesin 1 regulates cilia length through an interaction with the Bardet-Biedl syndrome related protein CCDC28B. Sci Rep. 2018;8(1):3019.
Seyama R, Tsuchida N, Okada Y, et al. Two families with TET3-related disorder showing neurodevelopmental delay with craniofacial dysmorphisms. J Hum Genet. 2021;67:157-164.
Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alfoldi J, Wang Q. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581:434-443.
Ng PC, Henikoff S. SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003;31(13):3812-3814.
Adzhubei IA, Schmidt S, Peshkin L, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7(4):248-249.
Schwarz JM, Rödelsperger C, Schuelke M, Seelow D. MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods. 2010;7:575-576.
Kircher M, Witten DM, Jain P, O'Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46(3):310-315.
Alegria A, Schmitt D, Ramos L, Abreu E, Santos C. Kyphomelic dysplasia, phenotypic variability and presence of a caudal appendage. Pediatr Radiol. 2002;32(12):910-911.
Pryde PG, Zelop C, Pauli RM. Prenatal diagnosis of isolated femoral bent bone skeletal dysplasia: problems in differential diagnosis and genetic counseling. Am J Med Genet A. 2003;117(3):203-206.
Spranger J, Hall BD, Häne B, Srivastava A, Stevenson RE. Spectrum of Schwartz-Jampel syndrome includes micromelic chondrodysplasia, kyphomelic dysplasia, and Burton disease. Am J Med Genet. 2000;94(4):287-295.
Le Merrer M, Cormier Daire V, Maroteaux P. Re-evaluation of kyphomelic dysplasia. Am J Med Genet A. 2003;120(2):289-291.
Corder WT, Hummel M, Miller C, Wilson NW. Association of kyphomelic dysplasia with severe combined immunodeficiency. Am J Med Genet. 1995;57(4):626-629.
Gan H, Xue W, Gao Y, et al. KIF5B modulates central spindle organization in late-stage cytokinesis in chondrocytes. Cell Biosci. 2019;9:85.
Santos-Ledo A, Garcia-Macia M, Campbell PD, Gronska M, Marlow FL. Kinesin-1 promotes chondrocyte maintenance during skeletal morphogenesis. PLoS Genet. 2017;13(7):e1006918.