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

Joakim Klar, Jens Schuster, Tahir Naeem Khan, Muhammad Jameel, Katrin Mäbert, Lars Forsberg, Shehla Anjum Baig, Shahid Mahmood Baig, Niklas Dahl

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)


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 immuneregulatory functions of LRP1.

Original languageEnglish
Pages (from-to)599-606
Number of pages8
JournalJournal of Medical Genetics
Issue number9
Publication statusPublished - 3 Jul 2015
Externally publishedYes


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