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De Novo Missense Variants in FBXW11 Cause Diverse Developmental Phenotypes Including Brain, Eye, and Digit Anomalies.

Abstract：

:The identification of genetic variants implicated in human developmental disorders has been revolutionized by second-generation sequencing combined with international pooling of cases. Here, we describe seven individuals who have diverse yet overlapping developmental anomalies, and who all have de novo missense FBXW11 variants identified by whole exome or whole genome sequencing and not reported in the gnomAD database. Their phenotypes include striking neurodevelopmental, digital, jaw, and eye anomalies, and in one individual, features resembling Noonan syndrome, a condition caused by dysregulated RAS signaling. FBXW11 encodes an F-box protein, part of the Skp1-cullin-F-box (SCF) ubiquitin ligase complex, involved in ubiquitination and proteasomal degradation and thus fundamental to many protein regulatory processes. FBXW11 targets include β-catenin and GLI transcription factors, key mediators of Wnt and Hh signaling, respectively, critical to digital, neurological, and eye development. Structural analyses indicate affected residues cluster at the surface of the loops of the substrate-binding domain of FBXW11, and the variants are predicted to destabilize the protein and/or its interactions. In situ hybridization studies on human and zebrafish embryonic tissues demonstrate FBXW11 is expressed in the developing eye, brain, mandibular processes, and limb buds or pectoral fins. Knockdown of the zebrafish FBXW11 orthologs fbxw11a and fbxw11b resulted in embryos with smaller, misshapen, and underdeveloped eyes and abnormal jaw and pectoral fin development. Our findings support the role of FBXW11 in multiple developmental processes, including those involving the brain, eye, digits, and jaw.

journal_name

Am J Hum Genet

journal_title

American journal of human genetics

authors

Holt RJ,Young RM,Crespo B,Ceroni F,Curry CJ,Bellacchio E,Bax DA,Ciolfi A,Simon M,Fagerberg CR,van Binsbergen E,De Luca A,Memo L,Dobyns WB,Mohammed AA,Clokie SJH,Zazo Seco C,Jiang YH,Sørensen KP,Andersen H,Sullivan

doi

10.1016/j.ajhg.2019.07.005

subject

Has Abstract

pub_date

2019-09-05 00:00:00

pages

640-657

issue

eissn

0002-9297

issn

1537-6605

pii

S0002-9297(19)30268-X

journal_volume

105

pub_type

杂志文章

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De Novo Missense Variants in FBXW11 Cause Diverse Developmental Phenotypes Including Brain, Eye, and Digit Anomalies.