SHROOM3 – Neural Tube Defects

SHROOM3 (HGNC:30422) encodes an actin-associated protein essential for epithelial cell shape changes during neural tube closure. Neural tube defects (NTDs), including anencephaly and spina bifida, affect ~1:1,000 births and have a multifactorial etiology; animal models have long implicated Shroom3 in neural tube formation and morphogenesis (Gene Symbol; Disease Name). Despite extensive model organism data, human evidence has been sparse until recent sequencing studies.

Genetic evidence now supports SHROOM3 as a monogenic contributor to NTDs. A human fetus with a homozygous SHROOM3 loss-of-function variant presented with anencephaly and cleft lip/palate, mirroring Shroom3 mouse mutants and indicating autosomal recessive inheritance (PMID:32621286). Whole-exome sequencing of 43 sporadic NTD trios identified two independent de novo protein-truncating variants in SHROOM3, significantly enriched compared to expected rates (PMID:25805808).

In total, three unrelated probands harboring SHROOM3 loss-of-function alleles (one homozygous, two heterozygous de novo) satisfy ClinGen moderate genetic evidence thresholds. These variants include c.1176C>G (p.Tyr392Ter) in SHROOM3, a recurrent nonsense change in anencephaly cases. No additional familial segregation beyond probands has been reported.

Functional studies corroborate a loss-of-function mechanism. Shroom3 null mice exhibit neural tube closure defects and craniofacial malformations concordant with human phenotypes. In vitro and in vivo models of the Rho-kinase binding-deficient Shroom3R1838C variant demonstrate that folic acid supplementation rescues defective apical constriction via MLCK and Src-kinase pathways, linking SHROOM3 function to known preventive therapy (PMID:30670450).

No reports dispute the association of SHROOM3 loss-of-function with NTDs. Taken together, genetic findings and mechanistic data establish SHROOM3 haploinsufficiency and complete loss-of-function as drivers of neural tube defects in humans.

Key Take-home: SHROOM3 loss-of-function variants cause neural tube defects via impaired apical constriction, supporting genetic diagnosis and potential folic acid–based interventions in affected families.

References

• Clinical genetics • 2020 • A homozygous pathogenic variant in SHROOM3 associated with anencephaly and cleft lip and palate. PMID:32621286
• American Journal of Human Genetics • 2015 • Exome sequencing of sporadic neural tube defect cases identifies de novo SHROOM3 truncating variants. PMID:25805808
• Biology open • 2019 • Folic acid modifies the shape of epithelial cells during morphogenesis via a Folr1 and MLCK dependent mechanism. PMID:30670450

Evidence Based Scoring (AI generated)