title: Whole exome sequencing identifies LRP1 as a pathogenic gene in autosomal recessive keratosis pilaris atrophicans.
abstract: BACKGROUND
  Keratosis pilaris atrophicans (KPA) is a group of rare genodermatoses characterised by perifollicular keratosis and inflammation that progresses to atrophy and scars of the facial skin. Keratosis pilaris of extensor areas of limbs is a common associated finding. Most cases with KPA are sporadic and no consistent inheritance pattern has been documented.
  
  
  METHODS
  A large consanguineous Pakistani pedigree segregating autosomal recessive KPA of a mixed type was subject to autozygosity mapping and whole exome sequencing. Quantification of mRNA and protein levels was performed on fibroblasts from affected individuals. Cellular uptake of the low-density lipoprotein (LDL) receptor-related protein 1 (LRP1) ligand α2-macroglobulin (α(2)M) was quantified using fluorescence confocal microscopy.
  
  
  RESULTS
  Genetic analyses identified a unique homozygous missense variant (K1245R) in the LRP1 in all affected family members. LRP1 encodes the LRP1, a multifunctional cell surface receptor with endocytic functions that belongs to the LDL receptor family. The LRP1 mRNA and LRP1 protein levels in fibroblasts of affected individuals were markedly reduced when compared with controls. Similarly, the LRP1-mediated cellular uptake of α(2)M was reduced in patient fibroblasts.
  
  
  CONCLUSIONS
  This is the first report on LRP1 as a pathogenic gene for autosomal recessive KPA and keratosis pilaris. The inflammatory characteristics of the KPA entity in our family suggest a link to the immune-regulatory functions of LRP1.
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Biomedical Centre, Uppsala, Sweden.
authors.forename: Joakim
authors.initials: J
authors.lastname: Klar
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Biomedical Centre, Uppsala, Sweden.
authors.forename: Jens
authors.initials: J
authors.lastname: Schuster
authors.affiliation: Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Pakistan Institute of Engineering and Applied Sciences (PIEAS), Faisalabad, Pakistan.
authors.forename: Tahir Naeem
authors.initials: TN
authors.lastname: Khan
authors.affiliation: Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Pakistan Institute of Engineering and Applied Sciences (PIEAS), Faisalabad, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Jameel
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Biomedical Centre, Uppsala, Sweden.
authors.forename: Katrin
authors.initials: K
authors.lastname: Mäbert
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Biomedical Centre, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Forsberg
authors.affiliation: Department of Pathology, Children's Hospital, Pakistan Institute of Medical Sciences, (PIMS), Islamabad, Pakistan.
authors.forename: Shehla Anjum
authors.initials: SA
authors.lastname: Baig
authors.affiliation: Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Pakistan Institute of Engineering and Applied Sciences (PIEAS), Faisalabad, Pakistan.
authors.forename: Shahid Mahmood
authors.initials: SM
authors.lastname: Baig
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Biomedical Centre, Uppsala, Sweden.
authors.forename: Niklas
authors.initials: N
authors.lastname: Dahl
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D025063:Chromosome Disorders / Q000235:genetics; D003241:Consanguinity; D007644:Darier Disease / Q000235:genetics*; D059472:Exome; D005091:Exons; D005138:Eyebrows / Q000002:abnormalities*; D005808:Genes, Recessive; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics*; D010154:Pakistan; D010375:Pedigree; D017354:Point Mutation; D017422:Sequence Analysis, DNA
chemical_list: C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1
keywords: Dermatology; Genetics