Variants in the <b><i>PNPLA1</i></b> Gene in Families with Autosomal Recessive Congenital Ichthyosis Reveal Clinical Significance

Abstract

The term autosomal recessive congenital ichthyosis (ARCI) is the subgroup of ichthyosis, which describes a highly heterogeneous group of genetic disorders of the skin characterized by cornification and defective keratinocytes differentiation associated with mutations in at least 14 genes including &lt;i&gt;PNPLA1&lt;/i&gt;. To study the molecular basis of the Pakistani kindreds (A and B) affected by ARCI, whole-exome sequencing (WES) in the DNA samples of affected members was performed followed by Sanger sequencing of the candidate gene to hunt down the disease-causing sequence variant/s. WES data analysis led to the identification of a novel nonsense sequence variant (c.892C&amp;#x3e;T; p.Arg298*, family A) and a recurrent missense variant (c.102C&amp;#x3e;A; p.Asp34Glu, family B) in &lt;i&gt;PNPLA1&lt;/i&gt; mapped to the ARCI locus in chromosome 6p21.31. Validation and cosegregation analysis of the variants in the remaining family members of the respective families were confirmed by Sanger sequencing. The current investigation expands the spectrum of &lt;i&gt;PNPLA1&lt;/i&gt; mutations and helps establish the proper clinico-genetic diagnosis and correct genotype-phenotype correlation.

PNPLA1-Mediated Acylceramide Biosynthesis and Autosomal Recessive Congenital Ichthyosis

“…It is characterized by extensive scaling of the epidermis and a genetic defect associated with keratinization, resulting in a significantly impaired skin barrier [ 34 ]. So far, mutations in at least 14 genes have been identified to be associated with ACRI, of which the PNPLA1 gene is implicated in the pathogenesis of ARCI10 [ 35 ]. Individuals with pathogenic variants in PNPLA1 usually present at birth with pyroclastic membranes, which then transform into a CIE phenotype with scalp involvement and hyperlinear palms and soles [ 36 ].…”

“…Various pure and compound heterozygous mutations in the PNPLA1 gene have been identified from a registry of human ichthyosis patients. To date, approximately 59 pathogenic mutations in the PNPLA1 gene have been reported ( Table 1 ) [ 2 , 4 , 24 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ]. These mutations include 35 missense mutations, four code-shifting mutations, eight nonsense mutations, four deletion mutations, three splice-site mutations, two early termination mutations, and one full code mutation.…”

Biallelic mutations in FLG, TGM1, and STS genes segregated with different types of ichthyoses in eight families of Pakistani origin

“…The non-syndromic types include ichthyosis vulgaris, X-linked ichthyosis (XLI), autosomal recessive congenital ichthyosis (ARCI), and keratinopathic ichthyosis. [1][2][3][4] The syndromic forms of ichthyosis are very rare and include: Netherton syndrome (Online Mendelian Inheritance in Man [OMIM]: 2565000, Sjogren-Larsson syndrome 5 and autosomal recessive congenital ichthyosis with hypotrichosis (ARIH). 6 Widespread Mendelian disorders of cornification and heritable types of ichthyoses are phenotypically extremely diverse conditions brought about by variants in numerous genes involved in keratinocyte differentiation, epidermal barrier development, and maintenance.…”

Congenital Ichthyosis: Clinical and Genetic Characteristics of the Disease

“…Дефектный кератин накапливается в цитоплазме, нарушая тем самым сборку кератиновых филаментов и разрушая кератиновую сеть[13,26] HI, LI, EI, CIE Белок ABC связывает и гидролизует АТФ, обеспечивая транспорт липидных молекул глюкозилцерамидов (GlcCer) во внеклеточное пространство через ламеллярные гранулы (LG) рогового слоя[28]. Дефект в гене ABCA12 приводит к нарушению транспорта липидов и избыточному накоплению GlcCer в клетках эпидермиса, изменению нормального строения пластинчатых (ламеллярных) гранул в эпидермоцитах зернистого слоя, вызывая гиперкератоз[29][30][31] сходство высокой степени с геном PNPLA2, обладающим триглицеридгидролазной активностью. Участвует в синтезе липидов и в их метаболизме во время формирования эпидермального барьера плода, в процессах кератинизации и терминальной дифференцировки кератиноцитов.…”

“…Участвует в синтезе липидов и в их метаболизме во время формирования эпидермального барьера плода, в процессах кератинизации и терминальной дифференцировки кератиноцитов. Дефект в гене приводит к нарушению указанных молекулярных процессов[31,32] LIPNЛипаза N LI, CIE Нарушение дифференцировки кератиноцитовCERS3Керамид-синтетаза 3 CERS3 LI, CIE Нарушение синтеза ацилцерамидов и связанных с белками церамидов, особенно с длинноцепочечными фрагментами[33]…”