title: Gene-Targeted Next Generation Sequencing Identifies PNPLA1 Mutations in Patients with a Phenotypic Spectrum of Autosomal Recessive Congenital Ichthyosis: The Impact of Consanguinity.
abstract: Autosomal recessive congenital ichthyosis is a heterogeneous group of disorders associated with mutations in at least nine distinct genes. To ascertain the molecular basis of ichthyosis patients in Iran, a country of approximately 80 million people with a high prevalence of customary consanguineous marriages, we have developed a gene-targeted next generation sequencing array consisting of 38 genes reported in association with ichthyosis phenotypes. In a subset of nine extended consanguineous families, we found homozygous missense mutations in the PNPLA1 gene, six of them being distinct and, to our knowledge, previously unpublished. This gene encodes an enzyme with lipid hydrolase activity, important for development and maintenance of the barrier function of the epidermis. These six mutations, as well as four previously published mutations, reside exclusively within the patatin-like subdomain of PNPLA1 containing the catalytic site. The mutations clustered around the active center of the enzyme or resided at the surface of the protein possibly involved in the protein-protein interactions. Clinical features of the patients showed considerable intra- and interfamilial heterogeneity. Knowledge of the specific mutations allows identification of heterozygous carriers, assisting in genetic counseling, prenatal testing, and preimplantation genetic diagnosis in extended families at risk of recurrence of this disorder, the incidence of which is significantly increased in consanguineous marriages.
authors.affiliation: Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA; Biotechnology Research Center, Department of Molecular Medicine, Pasteur Institute of Iran, Tehran, Iran.
authors.forename: Hassan
authors.initials: H
authors.lastname: Vahidnezhad
authors.affiliation: Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA; Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Leila
authors.initials: L
authors.lastname: Youssefian
authors.affiliation: Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Amir Hossein
authors.initials: AH
authors.lastname: Saeidian
authors.affiliation: Biotechnology Research Center, Department of Molecular Medicine, Pasteur Institute of Iran, Tehran, Iran; Kawsar Human Genetics Research Center, Tehran, Iran.
authors.forename: Sirous
authors.initials: S
authors.lastname: Zeinali
authors.affiliation: Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Parvin
authors.initials: P
authors.lastname: Mansouri
authors.affiliation: Department of Dermatology, Children's Medical Center, Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Soheila
authors.initials: S
authors.lastname: Sotoudeh
authors.affiliation: Skin Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Mohammadreza
authors.initials: M
authors.lastname: Barzegar
authors.affiliation: Department of Genetics, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
authors.forename: Javad
authors.initials: J
authors.lastname: Mohammadi-Asl
authors.affiliation: Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran; Department of Molecular Systems Biology, Cell Sciences Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
authors.forename: Razieh
authors.initials: R
authors.lastname: Karamzadeh
authors.affiliation: Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Maryam
authors.initials: M
authors.lastname: Abiri
authors.affiliation: Sidney Kimmel Cancer Center, Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: McCormick
authors.affiliation: Sidney Kimmel Cancer Center, Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA; Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Fortina
authors.affiliation: Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA; Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. Electronic address: Jouni.Uitto@jefferson.edu.
authors.forename: Jouni
authors.initials: J
authors.lastname: Uitto
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D005808:Genes, Recessive; D056726:Genetic Association Studies; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D017490:Ichthyosis, Lamellar / Q000235:genetics*; D008049:Lipase / Q000235:genetics*; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D055815:Young Adult; D000217:Acyltransferases; D010740:Phospholipases
chemical_list: D008049:Lipase; C549684:PNPLA1 protein, human; D000217:Acyltransferases; D010740:Phospholipases