WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins. Hum Genet 2021 Dec;140(12):1775-1789
Date
10/14/2021Pubmed ID
34642815Pubmed Central ID
PMC9241141DOI
10.1007/s00439-021-02384-yScopus ID
2-s2.0-85117037209 (requires institutional sign-in at Scopus site) 3 CitationsAbstract
Missense variants located in the N-terminal region of WDR37 were recently identified to cause a multisystemic syndrome affecting neurological, ocular, gastrointestinal, genitourinary, and cardiac development. WDR37 encodes a WD40 repeat-containing protein of unknown function. We identified three novel WDR37 variants, two likely pathogenic de novo alleles and one inherited variant of uncertain significance, in individuals with phenotypes overlapping those previously reported but clustering in a different region of the protein. The novel alleles are C-terminal to the prior variants and located either within the second WD40 motif (c.659A>G p.(Asp220Gly)) or in a disordered protein region connecting the second and third WD40 motifs (c.778G>A p.(Asp260Asn) and c.770C>A p.(Pro257His)). The three novel mutants showed normal cellular localization but lower expression levels in comparison to wild-type WDR37. To investigate the normal interactions of WDR37, we performed co-immunoprecipitation and yeast two-hybrid assays. This revealed the ability of WDR37 to form homodimers and to strongly bind PACS1 and PACS2 phosphofurin acidic cluster sorting proteins; immunocytochemistry confirmed colocalization of WDR37 with PACS1 and PACS2 in human cells. Next, we analyzed previously reported and novel mutants for their ability to dimerize with wild-type WDR37 and bind PACS proteins. Interaction with wild-type WDR37 was not affected for any variant; however, one novel mutant, p.(Asp220Gly), lost its ability to bind PACS1 and PACS2. In summary, this study presents a novel region of WDR37 involved in human disease, identifies PACS1 and PACS2 as major binding partners of WDR37 and provides insight into the functional effects of various WDR37 variants.
Author List
Sorokina EA, Reis LM, Thompson S, Agre K, Babovic-Vuksanovic D, Ellingson MS, Hasadsri L, van Bever Y, Semina EVAuthors
Elena V. Semina PhD Chief, Professor in the Ophthalmology and Visual Sciences department at Medical College of WisconsinElena A. Sorokina Research Scientist I in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Abnormalities, MultipleAdolescent
Animals
Cells, Cultured
Child
Child, Preschool
Cognitive Dysfunction
Female
Humans
Male
Mutant Proteins
Nuclear Proteins
Pedigree
Protein Binding
Syndrome
Two-Hybrid System Techniques
Vesicular Transport Proteins
