Titre
Bi-allelic Variants in DYNC1I2 Cause Syndromic Microcephaly with Intellectual Disability, Cerebral Malformations, and Dysmorphic Facial Features.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Ansar, M.
Auteure/Auteur
Ullah, F.
Auteure/Auteur
Paracha, S.A.
Auteure/Auteur
Adams, D.J.
Auteure/Auteur
Lai, A.
Auteure/Auteur
Pais, L.
Auteure/Auteur
Iwaszkiewicz, J.
Auteure/Auteur
Millan, F.
Auteure/Auteur
Sarwar, M.T.
Auteure/Auteur
Agha, Z.
Auteure/Auteur
Shah, S.F.
Auteure/Auteur
Qaisar, A.A.
Auteure/Auteur
Falconnet, E.
Auteure/Auteur
Zoete, V.
Auteure/Auteur
Ranza, E.
Auteure/Auteur
Makrythanasis, P.
Auteure/Auteur
Santoni, F.A.
Auteure/Auteur
Ahmed, J.
Auteure/Auteur
Katsanis, N.
Auteure/Auteur
Walsh, C.
Auteure/Auteur
Davis, E.E.
Auteure/Auteur
Antonarakis, S.E.
Auteure/Auteur
Liens vers les personnes
ISSN
1537-6605
Statut éditorial
Publié
Date de publication
2019-06-06
Volume
104
Numéro
6
Première page
1073
Dernière page/numéro d’article
1087
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Résumé
Cargo transport along the cytoplasmic microtubular network is essential for neuronal function, and cytoplasmic dynein-1 is an established molecular motor that is critical for neurogenesis and homeostasis. We performed whole-exome sequencing, homozygosity mapping, and chromosomal microarray studies in five individuals from three independent pedigrees and identified likely-pathogenic variants in DYNC1I2 (Dynein Cytoplasmic 1 Intermediate Chain 2), encoding a component of the cytoplasmic dynein 1 complex. In a consanguineous Pakistani family with three affected individuals presenting with microcephaly, severe intellectual disability, simplification of cerebral gyration, corpus callosum hypoplasia, and dysmorphic facial features, we identified a homozygous splice donor site variant (GenBank: NM_001378.2:c.607+1G>A). We report two additional individuals who have similar neurodevelopmental deficits and craniofacial features and harbor deleterious variants; one individual bears a c.740A>G (p.Tyr247Cys) change in trans with a 374 kb deletion encompassing DYNC1I2, and an unrelated individual harbors the compound-heterozygous variants c.868C>T (p.Gln290 <sup>∗</sup> ) and c.740A>G (p.Tyr247Cys). Zebrafish larvae subjected to CRISPR-Cas9 gene disruption or transient suppression of dync1i2a displayed significantly altered craniofacial patterning with concomitant reduction in head size. We monitored cell death and cell cycle progression in dync1i2a zebrafish models and observed significantly increased apoptosis, likely due to prolonged mitosis caused by abnormal spindle morphology, and this finding offers initial insights into the cellular basis of microcephaly. Additionally, complementation studies in zebrafish demonstrate that p.Tyr247Cys attenuates gene function, consistent with protein structural analysis. Our genetic and functional data indicate that DYNC1I2 dysfunction probably causes an autosomal-recessive microcephaly syndrome and highlight further the critical roles of the dynein-1 complex in neurodevelopment.
PID Serval
serval:BIB_29D795794213
PMID
Date de création
2019-05-20T11:52:21.278Z
Date de création dans IRIS
2025-05-20T18:45:20Z