Whole exome sequencing identifies LRP1 as a pathogenic gene in autosomal recessive keratosis pilaris atrophicans

J Med Genet. 2015 Sep;52(9):599-606. doi: 10.1136/jmedgenet-2014-102931. Epub 2015 Jul 3.

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.

Keywords: Dermatology; Genetics.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Chromosome Disorders / genetics
  • Consanguinity
  • Darier Disease / genetics*
  • Exome
  • Exons*
  • Eyebrows / abnormalities*
  • Genes, Recessive
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-1 / genetics*
  • Pakistan
  • Pedigree
  • Point Mutation*
  • Sequence Analysis, DNA

Substances

  • LRP1 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-1

Supplementary concepts

  • Burnett Schwartz Berberian syndrome