Lamin B receptor-related disorder is associated with a spectrum of skeletal dysplasia phenotypes

• Published in: Bone (New York, N.Y.) Vol. 120; pp. 354 - 363
• Main Authors: Thompson, Eliza, Abdalla, Ebtesam, Superti-Furga, Andrea, McAlister, William, Kratz, Lisa, Unger, Sheila, Royer-Bertrand, Beryl, Campos-Xavier, Belinda, Mittaz-Crettol, Laureane, Amin, Asmaa K., DeSanto, Cori, Wilson, David B., Douglas, Ganka, Kozel, Beth, Shinawi, Marwan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2019
• Subjects: Adult; Base Sequence; Child; Child, Preschool; Evolution, Molecular; Female; Genetic Variation; Greenberg dysplasia; Humans; Infant; Infant, Newborn; Lamin B Receptor; LBR; Lymphocytes - metabolism; Male; Osteochondrodysplasias - diagnostic imaging; Osteochondrodysplasias - metabolism; Osteochondrodysplasias - pathology; Pedigree; Pelger-Huët anomaly; Phenotype; Receptors, Cytoplasmic and Nuclear - genetics; Rhizomelic shortening; Skeletal dysplasia; Lamin B receptor; Pelger-Huët anomaly; Skeletal dysplasia; Greenberg dysplasia; LBR; Rhizomelic shortening
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2018.11.006

LBR (Lamin B Receptor) encodes a bifunctional protein important for cholesterol biosynthesis and heterochromatin organization on the inner nuclear membrane. Pathogenic variants in LBR are associated with marked phenotypic variability, ranging from the benign Pelger-Huët anomaly to lethal Greenberg Dysplasia. We performed trio exome sequencing (ES) on two patients with atypical variants of skeletal dysplasia and their unaffected parents. Patient 1 exhibited frontal bossing, mid-face hypoplasia, short stature with rhizomelic limb shortening, and relative macrocephaly at birth. Although remained short, Patient 1 later showed spontaneous improvement in her skeletal findings. Exome sequencing revealed two novel variants in LBR, c.1504C > G (p.Arg502Gly) in exon 12 and c.1748G > T (p.Arg583Leu) in exon 14, which were inherited from her unaffected father and mother, respectively. Sterol analysis revealed an increased level of cholesta‑8,14‑dien‑3β‑ol to 2.9% of total sterols, consistent with a functional deficiency of 3β‑hydroxysterol Δ14‑reductase. Patient 2 presented at birth with short stature and marked rhizomelic limb shortening but later exhibited decreasing severity of shortening of the long bones and improvement in the radiographic skeletal abnormalities although he continued to be significantly short at age 10 years. Exome sequencing revealed that Patient 2 is homozygous for a pathogenic variant c.1534C > T (p.Arg512Trp) in exon 12 of LBR, which was inherited from his unaffected consanguineous parents. This report provides further evidence for a phenotypic spectrum of LBR-associated disorders and expands the genotypic spectrum by describing 3 novel disease-causing variants that have not been previously associated with a disease. Moreover, our data on Patient 1 demonstrate that variants throughout the gene appear to influence both the sterol reductase and nuclear functions of LBR. •Pathologic variants in LBR cause Pelger-Huët anomaly and skeletal dysplasia.•Lethal Greenberg Dysplasia was the skeletal entity originally associated with LBR but two individuals with non-lethal bone dysplasia were subsequently reported.•Three novel LBR disease-causing variants are described in two patients who have non-lethal skeletal dysplasia with short stature and distinct feature of spontaneously improving rhizomelic limb shortening.•LBR-related conditions encompass a spectrum of skeletal phenotypes, probably reflecting the severity of the biochemical abnormality.•Both the sterol reductase and chromatin anchoring functionalities of LBR contribute to skeletal dysplasia and nuclear shape phenotype.