Biallelic variants in FBXL3 cause intellectual disability, delayed motor development and short stature.

Détails

ID Serval
serval:BIB_CC3DB25E32E9
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Biallelic variants in FBXL3 cause intellectual disability, delayed motor development and short stature.
Périodique
Human molecular genetics
Auteur(s)
Ansar M., Paracha S.A., Serretti A., Sarwar M.T., Khan J., Ranza E., Falconnet E., Iwaszkiewicz J., Shah S.F., Qaisar A.A., Santoni F.A., Zoete V., Megarbane A., Ahmed J., Colombo R., Makrythanasis P., Antonarakis S.E.
ISSN
1460-2083 (Electronic)
ISSN-L
0964-6906
Statut éditorial
Publié
Date de publication
15/03/2019
Peer-reviewed
Oui
Volume
28
Numéro
6
Pages
972-979
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
FBXL3 (F-Box and Leucine Rich Repeat Protein 3) encodes a protein that contains an F-box and several tandem leucine-rich repeats (LRR) domains. FBXL3 is part of the SCF (Skp1-Cullin-F box protein) ubiquitin ligase complex that binds and leads to phosphorylation-dependent degradation of the central clock protein cryptochromes (CRY1 and CRY2) by the proteasome and its absence causes circadian phenotypes in mice and behavioral problems. No FBXL3-related phenotypes have been described in humans. By a combination of exome sequencing and homozygosity mapping, we analyzed two consanguineous families with intellectual disability and identified homozygous loss-of-function (LoF) variants in FBXL3. In the first family, from Pakistan, an FBXL3 frameshift variant [NM_012158.2:c.885delT:p.(Leu295Phefs*25)] was the onlysegregating variant in five affected individuals in two family loops (LOD score: 3.12). In the second family, from Lebanon, we identified a nonsense variant [NM_012158.2:c.445C>T:p.(Arg149*)]. In a third patient from Italy, a likely deleterious non-synonymous variant [NM_012158.2:c.1072T>C:p.(Cys358Arg)] was identified in homozygosity. Protein 3D modeling predicted that the Cys358Arg change influences the binding with CRY2 by destabilizing the structure of the FBXL3, suggesting that this variant is also likely to be LoF. The eight affected individuals from the three families presented with a similar phenotype that included intellectual disability, developmental delay, short stature and mild facial dysmorphism, mainly large nose with a bulbous tip. The phenotypic similarity and the segregation analysis suggest that FBXL3 biallelic, LoF variants link this gene with syndromic autosomal recessive developmental delay/intellectual disability.
Pubmed
Web of science
Création de la notice
04/01/2019 14:50
Dernière modification de la notice
20/08/2019 16:46
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