ClinVar

In 4 affected children from a consanguineous Pakistani family with a mixed type of keratosis pilaris atrophicans (KPA; 604093), Klar et al. (2015) identified homozygosity for a c.3734A-G transition (c.3734A-G, NM_002332.2) in exon 23 of the LRP1 gene, resulting in a lys1245-to-arg (K1245R) substitution at a highly conserved residue within the sixth epidermal growth factor (EGF)-like domain. The mutation segregated fully with disease in the family and was not found in 200 Swedish or 200 Pakistani control chromosomes, in 900 in-house exomes, or in the dbSNP, EVS, ESP, or ExAC databases. Analysis of mRNA from patient fibroblast cultures showed a 5-fold reduction in LRP1 mRNA compared to age-matched controls; immunostaining and fluorescence confocal microscopy confirmed significantly reduced LRP1 levels in patient cells compared to controls. In addition, there was a marked reduction in cellular uptake of the known LRP1 ligand A2M (103950) in patient fibroblasts compared to controls, and intracellular A2M levels were reduced beyond what would be expected from the LRP1 levels (p = 0.0017) compared to controls, suggesting that binding properties of LRP1 to A2M were altered in the patients.