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Sixteen novel mutations in PNPLA 1 in patients with autosomal recessive congenital ichthyosis reveal the importance of an extended patatin domain in PNPLA 1 that is essential for proper human skin barrier function
Author(s) -
Zimmer A.D.,
Kim G.J.,
Hotz A.,
Bourrat E.,
Hausser I.,
Has C.,
Oji V.,
Stieler K.,
Vahlquist A.,
Kunde V.,
Weber B.,
Radner F.P.W.,
LeclercMercier S.,
Schlipf N.,
Demmer P.,
Küsel J.,
Fischer J.
Publication year - 2017
Publication title -
british journal of dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.304
H-Index - 179
eISSN - 1365-2133
pISSN - 0007-0963
DOI - 10.1111/bjd.15308
Subject(s) - congenital ichthyosis , ichthyosis , genetics , sanger sequencing , mutation , biology , genetic heterogeneity , phenotype , gene , massive parallel sequencing , dna sequencing
Summary Background Autosomal recessive congenital ichthyosis ( ARCI ) is a genetically heterogeneous group of rare Mendelian skin disorders characterized by cornification and differentiation defects of keratinocytes. Mutations in nine genes including PNPLA 1 are known to cause nonsyndromic forms of ARCI . To date, only 10 distinct pathogenic mutations in PNPLA 1 have been reported. Objectives To identify new causative PNPLA 1 mutations. Methods We screened genetically unresolved cases, including our ARCI collection, comprising more than 700 families. Screening for mutations was performed either by direct Sanger sequencing or in combination with a multigene panel, followed by sequence and mutation analysis. Results Here we report on 16 novel mutations present in patients from 17 families. While all previously reported mutations and most of our novel mutations are located within the core patatin domain, we report five novel PNPLA 1 mutations that are downstream of this domain. Thus, as recently described for PNPLA 2 , we hypothesize that a region larger than the core domain is required for full enzymatic activity of PNPLA 1 in human skin barrier formation. Conclusions We estimate the frequency of PNPLA 1 mutations among patients with ARCI to be around 3%. Most of our patients were born as collodion babies and showed a relatively mild ichthyosis phenotype. In four unrelated patients we observed a cyclic scaling course, which seems to be a potential phenotypic variation in a small percentage of patients with PNPLA 1 mutations. The variability of the clinical manifestations and the lack of typical clinical features are specific for patients with PNPLA 1 mutations, and emphasize the importance of DNA sequencing for differential diagnosis of ARCI s.