Identification of a novel<i>PNPLA1</i>mutation in a Spanish family with autosomal recessive congenital ichthyosis

Fachal, Laura; Rodríguez-Pazos, L.; Ginarte, Manuel; Carracedo, Ángel; Toribio, Jaime; Vega, Ana

doi:10.1111/bjd.12757

Cited by 23 publications

(32 citation statements)

References 6 publications

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“…Sequence variants in the PNPLA1 gene abolish lipid droplet accumulation in the keratinocytes suggesting PNPLA1 function not in triglyceride hydrolase activity but in glycerophospholipid synthesis or remodelling, which could be mediated by acyl-CoA-dependent or independent acyltransferase activity. 3 All the four mutations including three reported previously 3,7 and the one (p.Asp34Glu) identified in the present study (Table 1) affect the same conserved patatin domain which features the catalytic dyad (Asp 172 and Ser53) and cause ARCI. 8 …”

Section: Editorsupporting

confidence: 57%

A novel missense variant in the PNPLA1 gene underlies congenital ichthyosis in three consanguineous families

Ahmad

Ansar

Mehmood

et al. 2015

Acad Dermatol Venereol

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Section: Editorsupporting

confidence: 57%

A novel missense variant in the PNPLA1 gene underlies congenital ichthyosis in three consanguineous families

Ahmad

Ansar

Mehmood

et al. 2015

Acad Dermatol Venereol

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“…Thus, affected dogs developed lamellar ichthyosis resembling human ARCI. Furthermore, we and others described PNPLA1 mutations in patients affected by ARCI (OMIM #615024) demonstrating the involvement of PNPLA1 in human ichthyoses (Ahmad et al, 2015; Fachal et al, 2014; Grall et al, 2012; Lee et al, 2016). However, the enzymatic function of PNPLA1 is unknown.…”

Section: Introductionmentioning

confidence: 56%

PNPLA1 Deficiency in Mice and Humans Leads to a Defect in the Synthesis of Omega-O-Acylceramides

Grond

Eichmann

Dubrac

et al. 2017

Journal of Investigative Dermatology

108

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Mutations in PNPLA1 have been identified as causative for autosomal recessive congenital ichthyosis in humans and dogs. So far, the underlying molecular mechanisms are unknown. In this study, we generated and characterized PNPLA1-deficient mice and found that PNPLA1 is crucial for epidermal sphingolipid synthesis. The absence of functional PNPLA1 in mice impaired the formation of omega-O-acylceramides and led to an accumulation of nonesterified omega-hydroxy-ceramides. As a consequence, PNPLA1-deficient mice lacked a functional corneocyte-bound lipid envelope leading to a severe skin barrier defect and premature death of newborn animals. Functional analyses of differentiated keratinocytes from a patient with mutated PNPLA1 demonstrated an identical defect in omega-O-acylceramide synthesis in human cells, indicating that PNPLA1 function is conserved among mammals and indispensable for normal skin physiology. Notably, topical application of epidermal lipids from wild-type onto Pnpla1-mutant mice promoted rebuilding of the corneocyte-bound lipid envelope, indicating that supplementation of ichthyotic skin with omega-O-acylceramides might be a therapeutic approach for the treatment of skin symptoms in individuals affected by omega-O-acylceramide deficiency.

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“…ABHD5 is a causative gene of Chanarin–Dorfman syndrome (also known as neutral lipid storage disease with ichthyosis (NLSD-I)), an autosomal recessive disease accompanied by ichthyosis, steatosis and other symptoms26. LIPN and PNPLA1 are ARCI-causative genes12242527, but their roles in skin barrier formation have not yet been revealed. Reasoning that since ABHD5, LIPN and PNPLA1 contain phospholipase/hydrolase domains and some proteins containing such domains act as acyltransferases or transacylases28, we chose them as candidates for acylceramide synthetic acyltransferases/transacylases.…”

Section: Resultsmentioning

confidence: 99%

“…However, there still remain several genes whose functions or pathogenic roles have not been revealed. For example, the functions of the ARCI-causative genes NIPAL4 (NIPA-like domain-containing protein 4) and PNPLA1 (patatin-like phospholipase domain-containing protein 1) are currently unclear122425.…”

mentioning

confidence: 99%

PNPLA1 is a transacylase essential for the generation of the skin barrier lipid ω-O-acylceramide

et al. 2017

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Lipids are the primary components of the skin permeability barrier, which is the body's most powerful defensive mechanism against pathogens. Acylceramide (ω-O-acylceramide) is a specialized lipid essential for skin barrier formation. Here, we identify PNPLA1 as the long-sought gene involved in the final step of acylceramide synthesis, esterification of ω-hydroxyceramide with linoleic acid, by cell-based assays. We show that increasing triglyceride levels by overproduction of the diacylglycerol acyltransferase DGAT2 stimulates acylceramide production, suggesting that triglyceride may act as a linoleic acid donor. Indeed, the in vitro analyses confirm that PNPLA1 catalyses acylceramide synthesis using triglyceride as a substrate. Mutant forms of PNPLA1 found in patients with ichthyosis exhibit reduced or no enzyme activity in either cell-based or in vitro assays. Altogether, our results indicate that PNPLA1 is directly involved in acylceramide synthesis as a transacylase, and provide important insights into the molecular mechanisms of skin barrier formation and of ichthyosis pathogenesis.

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Identification of a novelPNPLA1mutation in a Spanish family with autosomal recessive congenital ichthyosis

Cited by 23 publications

References 6 publications

A novel missense variant in the PNPLA1 gene underlies congenital ichthyosis in three consanguineous families

A novel missense variant in the PNPLA1 gene underlies congenital ichthyosis in three consanguineous families

PNPLA1 Deficiency in Mice and Humans Leads to a Defect in the Synthesis of Omega-O-Acylceramides

PNPLA1 is a transacylase essential for the generation of the skin barrier lipid ω-O-acylceramide

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