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Bi-allelic Mutations in FAM149B1 Cause Abnormal Primary Cilium and a Range of Ciliopathy Phenotypes in Humans.

Abstract：

:Ciliopathies are clinical disorders of the primary cilium with widely recognized phenotypic and genetic heterogeneity. In two Arab consanguineous families, we mapped a ciliopathy phenotype that most closely matches Joubert syndrome (hypotonia, developmental delay, typical facies, oculomotor apraxia, polydactyly, and subtle posterior fossa abnormalities) to a single locus in which a founder homozygous truncating variant in FAM149B1 was identified by exome sequencing. We subsequently identified a third Arab consanguineous multiplex family in which the phenotype of Joubert syndrome/oral-facial-digital syndrome (OFD VI) was found to co-segregate with the same founder variant in FAM149B1. Independently, autozygosity mapping and exome sequencing in a consanguineous Turkish family with Joubert syndrome highlighted a different homozygous truncating variant in the same gene. FAM149B1 encodes a protein of unknown function. Mutant fibroblasts were found to have normal ciliogenesis potential. However, distinct cilia-related abnormalities were observed in these cells: abnormal accumulation IFT complex at the distal tips of the cilia, which assumed bulbous appearance, increased length of the primary cilium, and dysregulated SHH signaling. We conclude that FAM149B1 is required for normal ciliary biology and that its deficiency results in a range of ciliopathy phenotypes in humans along the spectrum of Joubert syndrome.

journal_name

Am J Hum Genet

journal_title

American journal of human genetics

authors

Shaheen R,Jiang N,Alzahrani F,Ewida N,Al-Sheddi T,Alobeid E,Musaev D,Stanley V,Hashem M,Ibrahim N,Abdulwahab F,Alshenqiti A,Sonmez FM,Saqati N,Alzaidan H,Al-Qattan MM,Al-Mohanna F,Gleeson JG,Alkuraya FS

doi

10.1016/j.ajhg.2019.02.018

subject

Has Abstract

pub_date

2019-04-04 00:00:00

pages

731-737

issue

4

eissn

0002-9297

issn

1537-6605

pii

S0002-9297(19)30063-1

journal_volume

104

pub_type

杂志文章

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