Dataset Information

Monoallelic BMP2 Variants Predicted to Result in Haploinsufficiency Cause Craniofacial, Skeletal, and Cardiac Features Overlapping Those of 20p12 Deletions.

ABSTRACT: Bone morphogenetic protein 2 (BMP2) in chromosomal region 20p12 belongs to a gene superfamily encoding TGF-?-signaling proteins involved in bone and cartilage biology. Monoallelic deletions of 20p12 are variably associated with cleft palate, short stature, and developmental delay. Here, we report a cranioskeletal phenotype due to monoallelic truncating and frameshift BMP2 variants and deletions in 12 individuals from eight unrelated families that share features of short stature, a recognizable craniofacial gestalt, skeletal anomalies, and congenital heart disease. De novo occurrence and autosomal-dominant inheritance of variants, including paternal mosaicism in two affected sisters who inherited a BMP2 splice-altering variant, were observed across all reported families. Additionally, we observed similarity to the human phenotype of short stature and skeletal anomalies in a heterozygous Bmp2-knockout mouse model, suggesting that haploinsufficiency of BMP2 could be the primary phenotypic determinant in individuals with predicted truncating variants and deletions encompassing BMP2. These findings demonstrate the important role of BMP2 in human craniofacial, skeletal, and cardiac development and confirm that individuals heterozygous for BMP2 truncating sequence variants or deletions display a consistent distinct phenotype characterized by short stature and skeletal and cardiac anomalies without neurological deficits.

SUBMITTER: Tan TY

PROVIDER: S-EPMC5812889 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Monoallelic BMP2 Variants Predicted to Result in Haploinsufficiency Cause Craniofacial, Skeletal, and Cardiac Features Overlapping Those of 20p12 Deletions.

Tan Tiong Yang TY Gonzaga-Jauregui Claudia C Bhoj Elizabeth J EJ Strauss Kevin A KA Brigatti Karlla K Puffenberger Erik E Li Dong D Xie LiQin L Das Nanditha N Skubas Ioanna I Deckelbaum Ron A RA Hughes Virginia V Brydges Susannah S Hatsell Sarah S Siao Chia-Jen CJ Dominguez Melissa G MG Economides Aris A Overton John D JD Mayne Valerie V Simm Peter J PJ Jones Bryn O BO Eggers Stefanie S Le Guyader Gwenaël G Pelluard Fanny F Haack Tobias B TB Sturm Marc M Riess Angelika A Waldmueller Stephan S Hofbeck Michael M Steindl Katharina K Joset Pascal P Rauch Anita A Hakonarson Hakon H Baker Naomi L NL Farlie Peter G PG

American journal of human genetics 20171130 6

Bone morphogenetic protein 2 (BMP2) in chromosomal region 20p12 belongs to a gene superfamily encoding TGF-β-signaling proteins involved in bone and cartilage biology. Monoallelic deletions of 20p12 are variably associated with cleft palate, short stature, and developmental delay. Here, we report a cranioskeletal phenotype due to monoallelic truncating and frameshift BMP2 variants and deletions in 12 individuals from eight unrelated families that share features of short stature, a recognizable c ...[more]

PMID: 29198724

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Project description:BackgroundBiallelic mutations in LIG4 encoding DNA-ligase 4 cause a rare immunodeficiency syndrome manifesting as infant-onset life-threatening and/or opportunistic infections, skeletal malformations, radiosensitivity and neoplasia. LIG4 is pivotal during DNA repair and during V(D)J recombination as it performs the final DNA-break sealing step.ObjectivesThis study explored whether monoallelic LIG4 missense mutations may underlie immunodeficiency and autoimmunity with autosomal dominant inheritance.MethodsExtensive flow-cytometric immune-phenotyping was performed. Rare variants of immune system genes were analyzed by whole exome sequencing. DNA repair functionality and T-cell-intrinsic DNA damage tolerance was tested with an ensemble of in vitro and in silico tools. Antigen-receptor diversity and autoimmune features were characterized by high-throughput sequencing and autoantibody arrays. Reconstitution of wild-type versus mutant LIG4 were performed in LIG4 knockout Jurkat T cells, and DNA damage tolerance was subsequently assessed.ResultsA novel heterozygous LIG4 loss-of-function mutation (p.R580Q), associated with a dominantly inherited familial immune-dysregulation consisting of autoimmune cytopenias, and in the index patient with lymphoproliferation, agammaglobulinemia, and adaptive immune cell infiltration into nonlymphoid organs. Immunophenotyping revealed reduced naive CD4+ T cells and low TCR-Vα7.2+ T cells, while T-/B-cell receptor repertoires showed only mild alterations. Cohort screening identified 2 other nonrelated patients with the monoallelic LIG4 mutation p.A842D recapitulating clinical and immune-phenotypic dysregulations observed in the index family and displaying T-cell-intrinsic DNA damage intolerance. Reconstitution experiments and molecular dynamics simulations categorize both missense mutations as loss-of-function and haploinsufficient.ConclusionsThis study provides evidence that certain monoallelic LIG4 mutations may cause human immune dysregulation via haploinsufficiency.

Project description:Microbes colonize anatomical sites in health to form commensal microbial communities (e.g., commensal gut microbiota, commensal skin microbiota, commensal oral microbiota). Commensal microbiota has indirect effects on host growth and maturation through interactions with the host immune system. The commensal microbiota was recently introduced as a novel regulator of skeletal growth and morphology at noncraniofacial sites. Further, we and others have shown that commensal gut microbes, such as segmented filamentous bacteria (SFB), contribute to noncraniofacial skeletal growth and maturation. However, commensal microbiota effects on craniofacial skeletal growth and morphology are unclear. To determine the commensal microbiota's role in craniofacial skeletal growth and morphology, we performed craniometric and bone mineral density analyses on skulls from 9-week-old female C57BL/6T germ-free (GF) mice (no microbes), excluded-flora (EF) specific-pathogen-free mice (commensal microbiota), and murine-pathogen-free (MPF) specific-pathogen-free mice (commensal microbiota with SFB). Investigations comparing EF and GF mice revealed that commensal microbiota impacted the size and shape of the craniofacial skeleton. EF versus GF mice exhibited an elongated gross skull length. Cranial bone length analyses normalized to skull length showed that EF versus GF mice had enhanced frontal bone length and reduced cranial base length. The shortened cranial base in EF mice was attributed to decreased presphenoid, basisphenoid, and basioccipital bone lengths. Investigations comparing MPF mice and EF mice demonstrated that commensal gut microbes played a role in craniofacial skeletal morphology. Cranial bone length analyses normalized to skull length showed that MPF versus EF mice had reduced frontal bone length and increased cranial base length. The elongated cranial base in MPF mice was due to enhanced presphenoid bone length. This work, which introduces the commensal microbiota as a contributor to craniofacial skeletal growth, underscores that noninvasive interventions in the gut microbiome could potentially be employed to modify craniofacial skeletal morphology. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Dataset Information

Monoallelic BMP2 Variants Predicted to Result in Haploinsufficiency Cause Craniofacial, Skeletal, and Cardiac Features Overlapping Those of 20p12 Deletions.

Publications

Monoallelic BMP2 Variants Predicted to Result in Haploinsufficiency Cause Craniofacial, Skeletal, and Cardiac Features Overlapping Those of 20p12 Deletions.

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