A novel claudin-10 mutation with a unique mechanism in two unrelated families with HELIX syndrome

Abstract

HELIX syndrome, characterized by hypohidrosis, electrolyte imbalance, lacrimal gland dysfunction, ichthyosis, and xerostomia due to claudin-10 (CLDN10) mutations, was recognized in 2017. Here we describe two unrelated Saudi families with this syndrome due to a novel CLDN10 mutation with a unique mechanism of CLDN10 inactivation. The two consanguineous families include 12 affected individuals (three siblings in family 1 and nine members in family 2). They presented with hypokalemia and the abovementioned features of HELIX syndrome. The underlying mutation was detected by whole exome sequencing, confirmed by Sanger sequencing and functionally indicated by RT-PCR, electrophysiological studies and immunohistochemical staining of transfected HEK293 and MDCK C7 cells, and skin and kidney biopsy tissues. A novel biallelic single nucleotide deletion was identified in exon 5 of CLDN10 (NM_182848.3: c.647delC, p.P216Lfs*19 for CLDN10a or NM_006984.4: c.653delC, p.P218Lfs*21 for CLDN10b). The mutation led to frameshift and extension of the original termination codon by nine amino acids with loss of the C-terminus pdz-binding motif. Functional studies showed mRNA degradation and protein retention in intracellular compartments and that the pdz-binding motif is crucial for proper localization of claudin-10 in tight junctions. In the kidney, claudin-10 was replaced by translocation of claudin-2 (proximal tubule) and claudin-19 (thick ascending limb), and in the sweat gland by claudin-3 and occludin. However, these claudins did not functionally compensate for loss of claudin-10. Thus, this novel CLDN10 mutation identified in these two families disrupted the Cterminus pdz-binding motif of claudin-10 causing HELIX syndrome.

Defective claudin-10 causes a novel variation of HELIX syndrome through compromised tight junction strand assembly

“…However, this is only the sixth reported instance of a homozygous CLDN10 variant associated with human disease and the fourth such variant affecting both protein isoforms. 1 , 2 , 3 , 4 , 5 In conclusion, we demonstrated that claudin-10a/b G163A/G165A causes a variation of HELIX syndrome based on defective claudin-10 TJ strand assembly. Thereby, claudin-10b is more severely affected than claudin-10a.…”

“…Of note, our data contrast with previous reports of xerostomia in HELIX patients. 2 , 3 , 4 , 5 , 28 However, quantitative assessment of saliva secretion has previously been performed solely by Hadj-Rabia et al 3 in three patients. Our dental findings indicate impaired enamel formation to be a novel phenotype of HELIX syndrome.…”

“…Recently, sequence variants in CLDN10 have been linked to a non-Bartter, non-Gitelman salt-losing tubulopathy with altered handling of divalent cations accompanied by dysfunctional salivary, sweat, and lacrimal glands. 1 , 2 , 3 , 4 , 5 The acronym HELIX has been coined for the associated clinical syndrome encompassing hypohidrosis, electrolyte imbalance, lacrimal gland dysfunction, ichthyosis, and xerostomia. 3 CLDN10 encodes the tight junction (TJ) protein claudin-10 which comes in two major isoforms, claudin-10a and claudin-10b.…”

Impact of claudin‐10 deficiency on amelogenesis: Lesson from a HELIX tooth

“…Amelogenesis imperfecta is also frequently found in patients with genetic disorders related to kidney, skin and many other organs 14,24,28,29 and the autosomal recessive inheritance (OMIM 617671; Prevalence: <1 /1,000,000) [30][31][32][33][34][35] . In addition, it has been reported that the patients with HELIX syndrome displayed a very early and severe enamel wear 32 .…”

“…Amelogenesis imperfecta is also frequently found in patients with genetic disorders related to kidney, skin, and other organs 16,26,30,31 . A disorder of this sort was recently found to be associated with loss‐of‐function variants of CLDN10 , resulting in the autosomal recessive HELIX syndrome characterized by hypohidrosis, electrolyte imbalance, lacrimal gland dysfunction, ichthyosis, and xerostomia (OMIM 617671; prevalence: <1/1,000,000) 32–37 . In addition, it has been reported that the patients with HELIX syndrome displayed a very early and severe enamel wear 34 .…”