TMEM260 – Structural Heart Defects and Renal Anomalies Syndrome

TMEM260 (HGNC:20185) encodes an ER-located O-mannosyltransferase and is implicated in autosomal recessive structural heart defects and renal anomalies syndrome (SHDRA) MONDO:0044321. Affected individuals present with persistent truncus arteriosus, ventricular septal defect and variable renal anomalies including elevated creatinine and renal cysts.

To date, twelve unrelated individuals have been reported with biallelic TMEM260 variants in SHDRA (PMID:34612517, PMID:37183566, PMID:28318500). These variants segregate in eight families with compound heterozygous or homozygous genotypes, confirming autosomal recessive inheritance (PMID:34612517, PMID:28318500).

The mutational spectrum is dominated by loss-of-function alleles (nonsense, frameshift, splice-site changes, multi-exon deletion) with a single missense variant c.344G>A (p.Arg115Lys) (PMID:34612517). A founder variant in East Asians, c.1617del (p.Leu447ValfsTer9), is recurrent in Japanese and Korean populations (PMID:38409496).

Functional studies demonstrate that TMEM260 selectively glycosylates IPT domains and that disease-causing mutations abolish O-mannosylation, leading to receptor maturation defects and abnormal epithelial morphogenesis in 3D cell models (PMID:37186866).

In vivo knockdown in zebrafish recapitulates neurological and cardiac defects, and rescue with human TMEM260 long isoform mRNA restores phenotype whereas the short isoform does not (PMID:28318500). These data support a loss-of-function mechanism via haploinsufficiency of TMEM260.

Collectively, robust segregation in eight families over >6 years and concordant cellular and animal model data establish a definitive TMEM260–SHDRA association with direct implications for genetic diagnosis and management of congenital heart and renal anomalies.

References

• Clinical Genetics • 2022 • Biallelic TMEM260 variants cause truncus arteriosus, with or without renal defects. PMID:34612517
• American Journal of Medical Genetics Part A • 2023 • PHACES-like syndrome with TMEM260 compound heterozygous variants. PMID:37183566
• American Journal of Human Genetics • 2017 • Mutations in TMEM260 Cause a Pediatric Neurodevelopmental, Cardiac, and Renal Syndrome. PMID:28318500
• Proceedings of the National Academy of Sciences • 2023 • The SHDRA syndrome-associated gene TMEM260 encodes a protein-specific O-mannosyltransferase. PMID:37186866
• Journal of Human Genetics • 2024 • The c.1617del variant of TMEM260 is identified as the most frequent single gene determinant for Japanese patients with a specific type of congenital heart disease. PMID:38409496

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