Extending the phenotype of BMPER-related skeletal dysplasias to ischiospinal dysostosis

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Abstract

Ischiospinal dysostosis (ISD) is a polytopic dysostosis characterized by ischial hypoplasia, multiple segmental anomalies of the cervicothoracic spine, hypoplasia of the lumbrosacral spine and occasionally associated with nephroblastomatosis. ISD is similar to, but milder than the lethal/semilethal condition termed diaphanospondylodysostosis (DSD), which is associated with homozygous or compound heterozygous mutations of bone morphogenetic protein-binding endothelial regulator protein ( BMPER) gene. Here we report for the first time biallelic BMPER mutations in two patients with ISD, neither of whom had renal abnormalities. Our data supports and further extends the phenotypic variability of BMPER-related skeletal disorders.

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Essential pro-Bmp roles of crossveinless 2 in mouse organogenesis.

Makoto Ikeya, Noriaki Sasai, Kazuki Nakao … (2006)

We here report essential roles of the Bmp-binding protein crossveinless 2 (Cv2; Bmper) in mouse organogenesis. In the null Cv2 mutant mouse, gastrulation occurs normally, but a number of defects are found in Cv2-expressing tissues such as the skeleton. Cartilage differentiation by Bmp4 treatment is reduced in cultured Cv2(-/-) fibroblasts. Moreover, the defects in the vertebral column and eyes of the Cv2(-/-) mouse are substantially enhanced by deleting one copy of the Bmp4 gene, suggesting a pro-Bmp role of Cv2 in the development of these organs. In addition, the Cv2(-/-) mutant exhibits substantial defects in Bmp-dependent processes of internal organ formation, such as nephron generation in the kidney. This kidney hypoplasia is synergistically enhanced by the additional deletion of Kcp (Crim2) which encodes a pro-Bmp protein structurally related to Cv2. This study demonstrates essential pro-Bmp functions of Cv2 for locally restricted signal enhancement in multiple aspects of mammalian organogenesis.

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BMPER mutation in diaphanospondylodysostosis identified by ancestral autozygosity mapping and targeted high-throughput sequencing.

Vincent Funari, Deborah Krakow, Lisette Nevarez … (2010)

Diaphanospondylodysostosis (DSD) is a rare, recessively inherited, perinatal lethal skeletal disorder. The low frequency and perinatal lethality of DSD makes assembling a large set of families for traditional linkage-based genetic approaches challenging. By searching for evidence of unknown ancestral consanguinity, we identified two autozygous intervals, comprising 34 Mbps, unique to a single case of DSD. Empirically testing for ancestral consanguinity was effective in localizing the causative variant, thereby reducing the genomic space within which the mutation resides. High-throughput sequence analysis of exons captured from these intervals demonstrated that the affected individual was homozygous for a null mutation in BMPER, which encodes the bone morphogenetic protein-binding endothelial cell precursor-derived regulator. Mutations in BMPER were subsequently found in three additional DSD cases, confirming that defects in BMPER produce DSD. Phenotypic similarities between DSD and Bmper null mice indicate that BMPER-mediated signaling plays an essential role in vertebral segmentation early in human development.

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A newly recognized autosomal recessive syndrome with abnormal vertebral ossification, rib abnormalities, and nephrogenic rests.

Federico Prefumo, Tessa Homfray, Iona Jeffrey … (2003)

We describe three cases of a severe malformation syndrome in siblings of both sexes. The characteristic features observed were absent intrauterine ossification of an apparently normal cartilaginous spinal column; rib abnormalities, with unossified segments and posterior gaps; thoracic hypoplasia; and multiple intralobar nephrogenic rests in the kidneys. This syndrome can be identified in early pregnancy by ultrasound scans due to the lack of ossification of the thoraco-lumbar spine and its association with increased nuchal translucency thickness. We suggest that this is a newly recognized autosomal recessive syndrome.

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Author and article information

Contributors

Giedre Grigelioniene: +46(0)8-517 739 21 , Giedre.Grigelioniene@ki.se

Tae-Joon Cho: +82-2-2072-2878 , tjcho@snu.ac.k

Journal

Journal ID (nlm-ta): Orphanet J Rare Dis

Journal ID (iso-abbrev): Orphanet J Rare Dis

Title: Orphanet Journal of Rare Diseases

Publisher: BioMed Central (London )

ISSN (Electronic): 1750-1172

Publication date (Electronic): 4 January 2016

Publication date PMC-release: 4 January 2016

Publication date Collection: 2016

Volume: 11

Electronic Location Identifier: 1

Affiliations

[ ]Department of Clinical Pathology and Clinical Genetics, and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden

[ ]Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

[ ]Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden

[ ]Division of Pediatric Orthopaedics, Seoul National University Children’s Hospital, Seoul, Republic of Korea

[ ]Department of Paediatrics and Department of Clinical and Experimental Medicine, Linköping University, Norrköping, Sweden

[ ]Department of Radiology, Woorisoa Children’s Hospital, Seoul, Republic of Korea

[ ]Department of Pediatric Imaging, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan

Article

Publisher ID: 380

DOI: 10.1186/s13023-015-0380-0

PMC ID: 4700746

PubMed ID: 26728142

SO-VID: 64ae4c5e-ffd6-4ed1-b5d0-aa2a74faff0d

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 10 September 2015

Date accepted : 17 December 2015

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100003725, National Research Foundation of Korea (KR);

Award ID: NRF-2014M3C9A2064684

Award Recipient : Tae-Joon Cho

Custom metadata

ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: ischiospinal dysostosis,diaphanospondylodysostosis,bmper,vertebral anomaly,ischial hypoplasia

Data availability:

ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: ischiospinal dysostosis, diaphanospondylodysostosis, bmper, vertebral anomaly, ischial hypoplasia

Extending the phenotype of BMPER-related skeletal dysplasias to ischiospinal dysostosis

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Most cited references 14

Essential pro-Bmp roles of crossveinless 2 in mouse organogenesis.

BMPER mutation in diaphanospondylodysostosis identified by ancestral autozygosity mapping and targeted high-throughput sequencing.

A newly recognized autosomal recessive syndrome with abnormal vertebral ossification, rib abnormalities, and nephrogenic rests.

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