WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins.

Autor: Sorokina EA; Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin, Children's of Wisconsin, Milwaukee, WI, USA., Reis LM; Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin, Children's of Wisconsin, Milwaukee, WI, USA., Thompson S; Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin, Children's of Wisconsin, Milwaukee, WI, USA., Agre K; Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA., Babovic-Vuksanovic D; Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA., Ellingson MS; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA., Hasadsri L; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA., van Bever Y; Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands., Semina EV; Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin, Children's of Wisconsin, Milwaukee, WI, USA. esemina@mcw.edu.; Departments of Ophthalmology and Visual Sciences and Cell Biology, Neurobiology and Anatomy, The Medical College of Wisconsin, Milwaukee, WI, USA. esemina@mcw.edu.
Jazyk: angličtina
Zdroj: Human genetics [Hum Genet] 2021 Dec; Vol. 140 (12), pp. 1775-1789. Date of Electronic Publication: 2021 Oct 12.
DOI: 10.1007/s00439-021-02384-y
Abstrakt: 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.
(© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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