Heterozygous Ile453Val codon mutation in exon 7, homozygous single nucleotide polymorphisms in intron 2 and 5 of cathepsin C are associated with Haim-Munk syndrome

Abstract

Objective:In the present study, we have investigated the genetic status of CTSC gene in a HMS subject, who along with her parents belonged to non-Jewish South Indian Dravidian community.Materials and Methods:Genomic deoxyribonucleic acid isolated from the peripheral blood of the subject was amplified with CTSC exon specific primers and were analyzed by direct sequencing.Results:Sequencing analysis identified Ile453Val mutation within exon 7 of CTSC gene in heterozygous condition, and two single nucleotide polymorphisms (SNPs) within intron 2 and 5 in homozygous condition.Conclusion:The present study has identified for the first time the association of Ile453Val mutation within exon 7 and the two SNPs in a subject with HMS.

One mutation, two phenotypes: a single nonsense mutation of theCTSCgene causes two clinically distinct phenotypes

“…The majority of these mutations (74 of 75; 99%), have been detected in patients with PLS, whereas only 4% (3 of 75), have been associated with HMS . Three mutations (c.145C/T, p.Gln49X, c.857A/G p.Gln286Arg and c.1357A/G p.Ile453Val) have been found in patients exhibiting both the PLS and the HMS phenotypes . However one of these, the p.Ile453Val (rs3888798) missense variant, is considered a polymorphism, and its eventual pathogenic role needs to be confirmed or excluded by further studies .…”

“…1,2,7,8 Three mutations (c.145C/T, p.Gln49X, c.857A/G p.Gln286Arg and c.1357A/G p.Ile453Val) have been found in patients exhibiting both the PLS and the HMS phenotypes. 1,12 However one of these, the p.Ile453Val (rs3888798) missense variant, is considered a polymorphism, and its eventual pathogenic role needs to be confirmed or excluded by further studies. 13 Only one mutation (c.587T/C p.Leu196Pro) has been associated exclusively with HMS.…”

Hereditary palmoplantar keratodermas. Part II: syndromic palmoplantar keratodermas – Diagnostic algorithm and principles of therapy

“…Recurrent skin infections are frequent additional findings. Onychogryphosis, arachnodactyly, acro‐osteolysis, pes planus (flatfoot) and permanent flexion contractures are pathognomonic of HMS …”

“…Specific PPK forms can be recognized by prominent mucosal involvement. In particular, severe periodontitis with premature tooth decay typifies two peculiar PPKs due to mutations of the cathepsin C (CTSC) gene [21][22][23][24] (Table S1): the Haim-Munk (HMS) and the Papillon-Lef evre (PLS) syndromes. [25][26][27] Cathepsin C is a lysosomal cysteine protease acting as an activator of serine proteases of immune and inflammatory cells 24 and possibly as a modulator of epithelial differentiation.…”

“…Onychogryphosis, arachnodactyly, acro-osteolysis, pes planus (flatfoot) and permanent flexion contractures are pathognomonic of HMS. 21,23,33 Palmoplantar keratoderma with periodontitis due to CTSC mutation (Papillon-Lef evre syndrome) PLS is a rare allelic disorder also due to recessive mutations in CTSC. 25,28 It usually manifests in early childhood and shares with HMS several (Table 3; Fig.…”