Faculty Collaboration Database

De Novo Missense Variants in WDR37 Cause a Severe Multisystemic Syndrome. Am J Hum Genet 2019 Aug 01;105(2):425-433

Date

07/23/2019

Pubmed ID

31327510

Pubmed Central ID

PMC6698968

DOI

10.1016/j.ajhg.2019.06.015

Scopus ID

2-s2.0-85069863703 (requires institutional sign-in at Scopus site)   22 Citations

Abstract

While genetic causes are known for many syndromes involving developmental anomalies, a large number of individuals with overlapping phenotypes remain undiagnosed. Using exome-sequencing analysis and review of matchmaker databases, we have discovered four de novo missense variants predicted to affect the N-terminal region of WDR37-p.Ser119Phe, p.Thr125Ile, p.Ser129Cys, and p.Thr130Ile-in unrelated individuals with a previously unrecognized syndrome. Features of WDR37 syndrome include the following: ocular anomalies such as corneal opacity/Peters anomaly, coloboma, and microcornea; dysmorphic facial features; significant neurological impairment with structural brain defects and seizures; poor feeding; poor post-natal growth; variable skeletal, cardiac, and genitourinary defects; and death in infancy in one individual. WDR37 encodes a protein of unknown function with seven predicted WD40 domains and no previously reported human pathogenic variants. Immunocytochemistry and western blot studies showed that wild-type WDR37 is localized predominantly in the cytoplasm and mutant proteins demonstrate similar protein levels and localization. CRISPR-Cas9-mediated genome editing generated zebrafish mutants with novel missense and frameshift alleles: p.Ser129Phe, p.Ser129Cys (which replicates one of the human variants), p.Ser129Tyr, p.Lys127Cysfs, and p.Gln95Argfs. Zebrafish carrying heterozygous missense variants demonstrated poor growth and larval lethality, while heterozygotes with frameshift alleles survived to adulthood, suggesting a potential dominant-negative mechanism for the missense variants. RNA-seq analysis of zebrafish embryos carrying a missense variant detected significant upregulation of cholesterol biosynthesis pathways. This study identifies variants in WDR37 associated with human disease and provides insight into its essential role in vertebrate development and possible molecular functions.

Author List

Reis LM, Sorokina EA, Thompson S, Muheisen S, Velinov M, Zamora C, Aylsworth AS, Semina EV

Author

Elena V. Semina PhD Chief, Professor in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Abnormalities, Multiple
Adult
Amino Acid Sequence
Animals
Child
Child, Preschool
Coloboma
Developmental Disabilities
Female
Humans
Infant
Infant, Newborn
Intellectual Disability
Male
Microfilament Proteins
Mutation, Missense
Nuclear Proteins
Sequence Homology
Syndrome
WD40 Repeats
Zebrafish