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Am J Hum Genet. 2019 Sep 5;105(3):640-657. doi: 10.1016/j.ajhg.2019.07.005. Epub 2019 Aug 8.

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

Author information

1
Faculty of Health and Life Sciences, Oxford Brookes University, Oxford OX3 0BP, UK.
2
Department of Cell and Developmental Biology, Biosciences, University College London, Gower St, London WC1E 6BT, UK; Institute of Ophthalmology, University College London, 11-34 Bath Street, London EC1V 9EL, UK.
3
Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
4
Genetic Medicine, University of California, San Francisco/Fresno, Fresno, CA 93701, USA.
5
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Scientific Institute for Research, Hospitalization, and Healthcare, 00146 Rome, Italy.
6
Department of Genetics, University Medical Center Utrecht, 3508 GA Utrecht, the Netherlands.
7
Department of Clinical Genetics, Odense University Hospital, 5000 Odense C, Denmark.
8
Molecular Genetics Unit, Fondazione Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy.
9
Unità Operativa Complessa di Pediatria e Patologia Neonatale, Ospedale San Martino, 32100 Belluno, Italy.
10
University of Washington, Seattle, WA 98195-6320, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle WA 98101, USA.
11
West Midlands Regional Genetics Laboratory, Birmingham Women's and Children's National Health Service Foundation Trust, Mindelsohn Way, Edgbaston, Birmingham B15 2TG, UK; Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, 11562 Cairo, Egypt.
12
West Midlands Regional Genetics Laboratory, Birmingham Women's and Children's National Health Service Foundation Trust, Mindelsohn Way, Edgbaston, Birmingham B15 2TG, UK.
13
UDEAR, Université de Toulouse, UMRS 1056 Institut National de la Santé et de la Recherche Médicale-Université Paul Sabatier, 31059 Toulouse, France.
14
Department of Pediatrics and Neurobiology, Program in Genetics and Genomics, Duke University School of Medicine, Durham, NC 27710, USA.
15
Hans Christian Andersen Children's Hospital, Odense University Hospital, 5000 Odense C, Odense, Denmark.
16
Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC 27710, USA.
17
Department of Clinical Affairs, Ambry Genetics, Aliso Viejo, CA 92656, USA.
18
Department of Neurology, Division of Neurogenetics Kennedy Krieger Institute, Baltimore, MD 21205, USA.
19
Centre for Genomics Research, Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, Cambridge, CB4 0WG, UK; Department of Medicine, the University of Melbourne, Melbourne, VIC 3010, Australia.
20
Mindich Child Health and Development Institute, Department of Pediatrics, and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
21
Department of Cell and Developmental Biology, Biosciences, University College London, Gower St, London WC1E 6BT, UK.
22
UDEAR, Université de Toulouse, UMRS 1056 Institut National de la Santé et de la Recherche Médicale-Université Paul Sabatier, 31059 Toulouse, France; Department of Medical Genetics, Purpan University Hospital, 31059 Toulouse, France.
23
Faculty of Health and Life Sciences, Oxford Brookes University, Oxford OX3 0BP, UK; West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's National Health Service Foundation Trust, Birmingham, B15 2TG, UK. Electronic address: nragge@brookes.ac.uk.

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.

KEYWORDS:

FBXW11; Noonan syndrome; WD40; Wnt; brain; development; digit; eye; hedgehog; neurodevelopment

PMID:
31402090
PMCID:
PMC6731360
[Available on 2020-03-05]
DOI:
10.1016/j.ajhg.2019.07.005
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