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

Eliza Thompson, Ebtesam Abdalla, Andrea Superti-Furga, William McAlister, Lisa Kratz, Sheila Unger, Beryl Royer-Bertrand, Belinda Campos-Xavier, Laureane Mittaz-Crettol, Asmaa K. Amin, Cori DeSanto, David B. Wilson, Ganka Douglas, Beth Kozel, Marwan Shinawi

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)354-363
Number of pages10
JournalBone
Volume120
DOIs
StatePublished - Mar 1 2019

Fingerprint

Exome
Phenotype
Sterols
Exons
Extremities
Parents
Parturition
Megalencephaly
Heterochromatin
Nuclear Envelope
Fathers
lamin B receptor
Oxidoreductases
Cholesterol
Mothers
Organizations
Bone and Bones
Genes
Proteins

Keywords

  • Greenberg dysplasia
  • Lamin B receptor
  • LBR
  • Pelger-Huët anomaly
  • Rhizomelic shortening
  • Skeletal dysplasia

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Histology

Cite this

Thompson, E., Abdalla, E., Superti-Furga, A., McAlister, W., Kratz, L., Unger, S., ... Shinawi, M. (2019). Lamin B receptor-related disorder is associated with a spectrum of skeletal dysplasia phenotypes. Bone, 120, 354-363. https://doi.org/10.1016/j.bone.2018.11.006

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

In: Bone, Vol. 120, 01.03.2019, p. 354-363.

Research output: Contribution to journalArticle

Thompson, E, Abdalla, E, Superti-Furga, A, McAlister, W, Kratz, L, Unger, S, Royer-Bertrand, B, Campos-Xavier, B, Mittaz-Crettol, L, Amin, AK, DeSanto, C, Wilson, DB, Douglas, G, Kozel, B & Shinawi, M 2019, 'Lamin B receptor-related disorder is associated with a spectrum of skeletal dysplasia phenotypes', Bone, vol. 120, pp. 354-363. https://doi.org/10.1016/j.bone.2018.11.006
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. / Lamin B receptor-related disorder is associated with a spectrum of skeletal dysplasia phenotypes. In: Bone. 2019 ; Vol. 120. pp. 354-363.
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abstract = "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-Hu{\"e}t 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.",
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AU - Kratz, Lisa

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AB - 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.

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