Contents lists available at ScienceDirect Bone journal homepage: www.elsevier.com/locate/bone A homozygous variant in the Lamin B receptor gene LBR results in a non- lethal skeletal dysplasia without Pelger-Huët anomaly Meagan Collins a,b , Valancy Miranda c , Justine Rousseau a , Lisa E. Kratz d , Philippe M. Campeau a,c, ⁎ a CHU Sainte Justine Research Center, Université de Montréal, Montreal, QC, Canada b Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada c Medical Genetics Division, Department of Pediatrics, Sainte-Justine University Hospital Center, Montreal, QC, Canada d Biochemical Genetics Laboratory, Kennedy Krieger Institute, Baltimore, MD, United States of America ARTICLE INFO Keywords: Skeletal dysplasia Lamin B receptor LBR Rhizomelia Mesomelia ABSTRACT Lamin B receptor, a member of the sterol reductase family, is an inner nuclear membrane protein which binds lamin B proteins and is involved in the organization of heterochromatin. Mutations in LBR have been associated with a variety of disorders, such as Pelger-Huët anomaly, a benign abnormality affecting neutrophils, and Greenberg Dysplasia, a lethal condition in the perinatal period. We identified a homozygous LBR missense mutation (NM_002296.4: c.1366C > G, p.(Leu456Val)) in two adult sisters with a Lamin B receptor-related disorder associated with a skeletal dysplasia milder than Greenberg Dysplasia. Individual 1 has short stature with short limbs (mostly rhizomelic for the upper extremities, and mesomelic for the lower extremities), limited elbow extension. She required Achilles tenotomy, and does not have facial dysmorphisms. Individual 2 has similar skeletal features, but also has bowed femurs, osteopenia, spastic paraplegia of the lower limbs, equi- novarus feet, a single kidney, neurogenic bladder, obstructive hydronephrosis, scoliosis and syndactyly of the toes. This report provides additional evidence of variability for Lamin B receptor-related disorders associated with a non-lethal skeletal dysplasia without Pelger-Huët anomaly. We describe a novel pathogenic variant that has not been previously associated with disease and demonstrate the effect of this variant on sterol C14-re- ductase activity. 1. Introduction The Lamin B receptor (LBR) protein, which is a bifunctional protein on the inner nuclear membrane that is involved in the organization of heterochromatin and synthesis of cholesterol, is encoded by the Lamin B receptor (LBR) gene (MIM* 600024) [1]. Pathogenic variants in LBR are associated with a spectrum of phenotypic variability including the be- nign Pelger-Huët anomaly (MIM# 169400) and the severe Greenberg Dysplasia (MIM# 215140) [2,3]. Pelger-Huët anomaly is characterized by hypolobulated neutrophil nuclei with coarse chromatin and is in- herited in a dominant and co-dominant fashion. Individuals with LBR variants and Pelger-Huët anomaly (MIM# 169400), either in isolation or associated with skeletal abnormalities, have been reported [4]. Pelger-Huët anomaly with mild skeletal anomalies (PHASK; MIM # 618019), also known as Regressive Spondylometaphyseal Dysplasia, is a disorder resulting in abnormal blood granulocyte nuclear shape, ac- companied by both short stature and other skeletal anomalies [5,6,9]. PHASK has been linked to homozygous mutations or compound heterozygous mutations in LBR [6]. Greenberg dysplasia is a rare, au- tosomal recessive dysplasia associated with fetal hydrops, marked shortening of long bones, moth-eaten appearance of bones on radio- graphy, and abnormal calcification [7,8]. Greenberg dysplasia is also referred to as Hydrops-Ectopic calcification-Moth-eaten (HEM) skeletal dysplasia [7,8]. Other rare, milder forms of skeletal dysplasia have been linked to additional variants in LBR [3,9]. Our report further adds to the spectrum of skeletal disease associated with LBR variants. Located on chromosome 1q42.12, LBR is widely expressed in a variety of tissues, including brain, bone, skin, and liver [1–3,10]. LBR is found in the inner nuclear membrane and the endoplasmic reticulum and has various domains which serve two different functions. The nu- cleoplasmic domain, which is encoded by exons 1–4, maintains the structural integrity of the lamin network and tethers heterochromatin to the inner nuclear membrane [3,11–13]. The transmembrane do- mains, encoded by exons 5–13, regulate sterol reductase activity [1,11–14]. Mutations within the transmembrane domains result in deficits of https://doi.org/10.1016/j.bone.2020.115601 Received 26 March 2020; Received in revised form 6 August 2020; Accepted 15 August 2020 ⁎ Corresponding author at: Medical Genetics Division, Department of Pediatrics, University Hospital Center Sainte-Justine, Montreal, QC, Canada. E-mail address: p.campeau@umontreal.ca (P.M. Campeau). Bone 141 (2020) 115601 Available online 19 August 2020 8756-3282/ © 2020 Elsevier Inc. All rights reserved. T