PNPLA1 Gene

The PNPLA1 gene (PNPLA1 stands for "Patatin Like Phospholipase Domain Containing 1") is a protein coding gene located on chromosome 6p21.31.

Diseases associated with PNPLA1 include:

• Ichthyosis, congenital, autosomal recessive 10 ACRI 10).

Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

The protein encoded by this gene belongs to the family of patatin-like phospholipases (PNPLA), which are characterized by the presence of a highly conserved so-called "patatin domain".

The human genome encodes nine enzymes belonging to the patatin-like phospholipase domain-containing lipase (PNPLA)/Ca2+-independent phospholipase A2 (iPLA2) family. Although most PNPLA/iPLA2 enzymes are widely distributed and act as (phospho)lipases on phospholipids or neutral lipids to play a homeostatic role in lipid metabolism, the function of PNPLA1 remained unknown until a few years ago. Only recently, mutations in the human PNPLA1 gene were shown to be associated with autosomal recessive congenital ichthyosis (ARCI) Pichery M et al (2017). PNPLA1 is specifically expressed in differentiated keratinocytes and plays a critical role in the biosynthesis of ω-O-acylceramide, a specific class of sphingolipids essential for skin barrier function. PNPLA1 functions as a unique transacylase that specifically transfers linoleic acid from triglyceride to ω-hydroxy fatty acid in ceramide resulting in ω-O-acylceramide (Hirabayashi Tet al. 2019).

Omega-hydroxyceramide transacylase involved in the synthesis of omega-O-acylceramides (esterified omega-hydroxyacyl sphingosine; EOS), which are extremely hydrophobic lipids involved in skin barrier formation. PNPA phospholipase catalyzes the final step in the synthesis of omega-O-acylceramides by transferring linoleic acid from triglycerides to an omega-hydroxyceramide. Omega-O-acylceramides are required for the biogenesis of lipid lamellae in the stratum corneum and the formation of the cornified lipid envelope, which is essential for the barrier function of the epidermis. These lipids also play a role in the differentiation of keratinocytes.

1. Arias-Pérez RD et al (2021) Ichthyosis: case report in a Colombian man with genetic alterations in ABCA12 and HRNR genes. BMC Med Genomics 14:140.
2. Hirabayashi Tet al. (2019) The role of PNPLA1 in ω-O-acylceramide synthesis and skin barrier function. Biochim Biophys Acta Mol Cell Biol Lipids 1864: 869-879.
3. Pichery M et al (2017) PNPLA1 defects in patients with autosomal recessive congenital ichthyosis and KO mice sustain PNPLA1 irreplaceable function in epidermal omega-O-acylceramide synthesis and skin permeability barrier. Hum Mol Genet 26:1787-1800.
4. Scott CA et al (2013) Harlequin ichthyosis: ABCA12 mutations underlie defective lipid transport, reduced protease regulation and skin-barrier dysfunction. Cell Tissue Res 351:281-288
5. Sun Q et al (2022) The genomic and phenotypic landscape of ichthyosis: An Analysis of 1000 Kindreds. JAMA Dermatol 158:16-25.
6. Vahidnezhad H et al (2017) Gene-Targeted Next Generation Sequencing Identifies PNPLA1 Mutations in Patients with a Phenotypic Spectrum of Autosomal Recessive Congenital Ichthyosis: The Impact of Consanguinity. J Invest Dermatol 137: 678-685.