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De Novo Missense Variants in WDR37 Cause a Severe Multisystemic Syndrome.
Reis, Linda M; Sorokina, Elena A; Thompson, Samuel; Muheisen, Sanaa; Velinov, Milen; Zamora, Carlos; Aylsworth, Arthur S; Semina, Elena V.
Affiliation
  • Reis LM; Department of Pediatrics, Children's Research Institute, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI 53226, USA.
  • Sorokina EA; Department of Pediatrics, Children's Research Institute, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI 53226, USA.
  • Thompson S; Department of Pediatrics, Children's Research Institute, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI 53226, USA.
  • Muheisen S; Department of Pediatrics, Children's Research Institute, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI 53226, USA.
  • Velinov M; Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
  • Zamora C; Department of Radiology, Division of Neuroradiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Aylsworth AS; Departments of Pediatrics and Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Semina EV; Department of Pediatrics, Children's Research Institute, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI 53226, USA; Departments of Ophthalmology and Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address: e
Am J Hum Genet ; 105(2): 425-433, 2019 08 01.
Article in En | MEDLINE | ID: mdl-31327510
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Abnormalities, Multiple / Nuclear Proteins / Developmental Disabilities / Coloboma / Mutation, Missense / WD40 Repeats / Intellectual Disability Type of study: Prognostic_studies Limits: Adult / Animals / Child / Child, preschool / Female / Humans / Infant / Male / Newborn Language: En Journal: Am J Hum Genet Year: 2019 Document type: Article Affiliation country: United States Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Abnormalities, Multiple / Nuclear Proteins / Developmental Disabilities / Coloboma / Mutation, Missense / WD40 Repeats / Intellectual Disability Type of study: Prognostic_studies Limits: Adult / Animals / Child / Child, preschool / Female / Humans / Infant / Male / Newborn Language: En Journal: Am J Hum Genet Year: 2019 Document type: Article Affiliation country: United States Country of publication: United States