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Whole exome sequencing identifies LRP1 as a pathogenic gene in autosomal recessive keratosis pilaris atrophicans
  1. Joakim Klar1,
  2. Jens Schuster1,
  3. Tahir Naeem Khan2,
  4. Muhammad Jameel2,
  5. Katrin Mäbert1,
  6. Lars Forsberg1,
  7. Shehla Anjum Baig3,
  8. Shahid Mahmood Baig2,
  9. Niklas Dahl1
  1. 1Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Biomedical Centre, Uppsala, Sweden
  2. 2Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Pakistan Institute of Engineering and Applied Sciences (PIEAS), Faisalabad, Pakistan
  3. 3Department of Pathology, Children's Hospital, Pakistan Institute of Medical Sciences, (PIMS), Islamabad, Pakistan
  1. Correspondence to Dr Niklas Dahl, Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, BMC, Box 815, Uppsala 752 37, Sweden; niklas.dahl{at}


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 (α2M) 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 α2M 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.

  • Genetics
  • Dermatology

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