CLDN10 – HELIX syndrome

HELIX syndrome is an autosomal recessive disorder caused by pathogenic variants in the tight junction gene CLDN10, characterized by Hypohidrosis, Electrolyte disturbances, hypoLacrimia, Ichthyosis, and Xerostomia. It typically presents in childhood with reduced sweating, dry skin, alacrima, and xerostomia, progressing to salt‐losing nephropathy in adulthood in a subset of cases ([PMID:38927623]).

In two unrelated consanguineous Saudi families, whole‐exome sequencing identified a homozygous frameshift deletion NM_006984.5:c.653del (p.Thr216LysfsTer23) in 12 affected individuals presenting with hypohidrosis, hypokalemia, lacrimal gland dysfunction, ichthyosis, and xerostomia ([PMID:33675844]). Functional assays including RT‐PCR, electrophysiology, and immunohistochemistry demonstrated mRNA degradation, intracellular retention of mutant claudin-10, and loss of the C-terminal PDZ-binding motif.

In the first Spanish family, two adult brothers from consanguineous parents with suspected ectodermal dysplasia were found to harbor a novel homozygous 8-base deletion, c.322_329del (p.Gly108_Ala139del), correlating with hypohidrosis, xerosis, mild ichthyosis, plantar keratosis, alacrima, xerostomia, and adult-onset salt‐losing nephropathy with hypokalemia and hypermagnesemia ([PMID:38927623]).

Across three unrelated families and 14 probands, all CLDN10 variants are loss-of-function deletions or frameshifts leading to truncated protein, segregating recessively with disease. The recurrent spectrum includes c.322_329del (p.Gly108_Ala139del) and c.653del (p.Thr216LysfsTer23).

Mechanistic studies in HEK293 and MDCK C7 cells and ex vivo skin and kidney biopsies confirmed that mutant claudin-10 fails to assemble into continuous tight junction strands, abrogating paracellular Na+ permeability and causing compensatory claudin translocation without functional rescue ([PMID:33675844]; [PMID:35873018]). Murine models lacking CLDN10 recapitulate electrolyte and urine concentrating defects, supporting a loss-of-function mechanism ([PMID:28674042]).

The genetic and experimental data satisfy ClinGen criteria for a Strong gene-disease association, with multiple unrelated probands, clear segregation, and concordant functional evidence. Early inclusion of CLDN10 in ectodermal dysplasia and renal salt-losing tubulopathy panels facilitates prompt diagnosis, guides management of glandular and renal manifestations, and enables accurate genetic counseling.

References

• Genes • 2024 • HELIX Syndrome, a Claudinopathy with Relevant Dermatological Manifestations: Report of Two New Cases. PMID:38927623
• Kidney international • 2021 • A novel claudin-10 mutation with a unique mechanism in two unrelated families with HELIX syndrome. PMID:33675844
• Journal of the American Society of Nephrology : JASN • 2017 • A Novel Hypokalemic-Alkalotic Salt-Losing Tubulopathy in Patients with CLDN10 Mutations. PMID:28674042
• Genes & diseases • 2022 • Defective claudin-10 causes a novel variation of HELIX syndrome through compromised tight junction strand assembly. PMID:35873018

Evidence Based Scoring (AI generated)