ORIGINAL ARTICLE Whole exome sequencing identifies LRP1 as a pathogenic gene in autosomal recessive keratosis pilaris atrophicans Joakim Klar, 1 Jens Schuster, 1 Tahir Naeem Khan, 2 Muhammad Jameel, 2 Katrin Mäbert, 1 Lars Forsberg, 1 Shehla Anjum Baig, 3 Shahid Mahmood Baig, 2 Niklas Dahl 1 1 Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Biomedical Centre, Uppsala, Sweden 2 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 3 Department of Pathology, Children’s Hospital, Pakistan Institute of Medical Sciences, (PIMS), Islamabad, Pakistan 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@igp.uu.se JK and JS contributed equally. Received 12 December 2014 Revised 27 May 2015 Accepted 14 June 2015 To cite: Klar J, Schuster J, Khan TN, et al. J Med Genet Published Online First: [ please include Day Month Year] doi:10.1136/ jmedgenet-2014-102931 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 α 2 - 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. INTRODUCTION Keratosis pilaris atrophicans (KPA) is a small group of follicular syndromes characterised by inflamma- tion and atrophy. 1 The morphological hallmarks are variable degrees of perifollicular inflammation, secondary scarring and/or alopecia. Three clinical entities of KPA are described: keratosis pilaris atro- phicans faciei (KPAF), keratosis follicularis spinu- losa decalvans (KFSD) and atrophoderma vermiculatum (AV). 1–3 However, affected indivi- duals may present with features that overlap between the three entities. The onset of KPAF is usually in infancy with erythema, follicular kerato- tic papules on the lateral parts of the eyebrows that may extend to the forehead as well as scarring alo- pecia. 2 KFSD also presents in infancy with papules primarily in the malar area, patchy scarring alope- cia of the scalp as well as the absence of eyebrows and eyelashes. 3 AV (MIM 209700) is considered a more severe form of KPA with a typical onset in late childhood or adolescence. The AV entity is characterised by erythema and follicular keratotic papules located on the cheeks, preauricular regions and forehead that may extend to the lips and ear- lobes. 4 The papules progress to pitted atrophic and depressed scars in a reticular or honeycomb pattern. Eyebrows, eyelashes and scalp are usually spared but eyebrows may sometimes be involved. The course of the three KPA entities is usually slowly progressive with poor response to treatment. Typical histopathological findings in KPA include follicular hyperkeratosis, various degrees of perifol- licular inflammation and atrophic hair follicles. The primary defects appear to be an abnormal keratini- sation of the upper part of the hair follicle leading to follicular plugs which may obstruct the growing hair shaft to produce a chronic inflammatory infil- trate with scarring below that level. 5 An abnormal keratinisation may precede follicular dystrophy in and around the pilosebaceous follicle. Keratosis pilaris (MIM 604093) with follicular plugging and atrophy of hair follicles of extensor areas of the limbs is a common associated finding. 24 The genet- ics behind KPA is unclear and most reported cases are sporadic. However, a few familial cases have been reported consistent with either autosomal dominant, autosomal recessive or X linked inherit- ance. 2–467 No gender or ethnical predilection has been reported for the disease. Here, we report findings from a large consanguin- eous family segregating isolated and autosomal recessive KPA of a mixed type and with similarities to both AVand KFSD. Furthermore, we show that a missense mutation in a highly conserved residue of the extracellular domain of low-density lipoprotein (LDL) receptor-related protein 1 (LRP1) segregates with the disease. The gene variant is associated with reduced levels of the protein as well as with reduced cellular uptake of α 2 -macroglobulin (α 2 M). Based on the role of LRP1 in inflammation, we suggest a pathogenic mechanism in our family caused by LRP1-mediated dysregulation of the inflammatory response. Klar J, et al. J Med Genet 2015;0:1–8. doi:10.1136/jmedgenet-2014-102931 1 New loci JMG Online First, published on July 3, 2015 as 10.1136/jmedgenet-2014-102931 Copyright Article author (or their employer) 2015. 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