The aggrecanopathies; an evolving phenotypic spectrum of human genetic skeletal diseases

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Abstract

The large chondroitin sulphated proteoglycan aggrecan ( ACAN) is the most abundant non-collagenous protein in cartilage and is essential for its structure and function. Mutations in ACAN result in a broad phenotypic spectrum of non-lethal skeletal dysplasias including spondyloepimetaphyseal dysplasia, spondyloepiphyseal dysplasia, familial osteochondritis dissecans and various undefined short stature syndromes associated with accelerated bone maturation. However, very little is currently known about the disease pathways that underlie these aggrecanopathies, although they are likely to be a combination of haploinsufficiency and dominant-negative (neomorphic) mechanisms. This review discusses the known human and animal aggrecanopathies in the context of clinical presentation and potential disease mechanisms.

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Nosology and Classification of Genetic Skeletal Disorders: 2010 Revision

Matthew Warman, Valerie Cormier-Daire, Christine Hall … (2011)

Genetic disorders involving the skeletal system arise through disturbances in the complex processes of skeletal development, growth and homeostasis and remain a diagnostic challenge because of their variety. The Nosology and Classification of Genetic Skeletal Disorders provides an overview of recognized diagnostic entities and groups them by clinical and radiographic features and molecular pathogenesis. The aim is to provide the Genetics, Pediatrics and Radiology community with a list of recognized genetic skeletal disorders that can be of help in the diagnosis of individual cases, in the delineation of novel disorders, and in building bridges between clinicians and scientists interested in skeletal biology. In the 2010 revision, 456 conditions were included and placed in 40 groups defined by molecular, biochemical, and/or radiographic criteria. Of these conditions, 316 were associated with mutations in one or more of 226 different genes, ranging from common, recurrent mutations to “private” found in single families or individuals. Thus, the Nosology is a hybrid between a list of clinically defined disorders, waiting for molecular clarification, and an annotated database documenting the phenotypic spectrum produced by mutations in a given gene. The Nosology should be useful for the diagnosis of patients with genetic skeletal diseases, particularly in view of the information flood expected with the novel sequencing technologies; in the delineation of clinical entities and novel disorders, by providing an overview of established nosologic entities; and for scientists looking for the clinical correlates of genes, proteins and pathways involved in skeletal biology. © 2011 Wiley-Liss, Inc.

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Nonsense-mediated mRNA decay - mechanisms of substrate mRNA recognition and degradation in mammalian cells.

Christoph Schweingruber, Simone Rufener, David Zünd … (2015)

The nonsense-mediated mRNA decay (NMD) pathway is well known as a translation-coupled quality control system that recognizes and degrades aberrant mRNAs with truncated open reading frames (ORF) due to the presence of a premature termination codon (PTC). However, a more general role of NMD in posttranscriptional regulation of gene expression is indicated by transcriptome-wide mRNA profilings that identified a plethora of physiological mRNAs as NMD targets. In this review, we focus on mechanistic aspects of target mRNA identification and degradation in mammalian cells, based on the available biochemical and genetic data, and point out knowledge gaps. Translation termination in a messenger ribonucleoprotein particle (mRNP) environment lacking necessary factors for proper translation termination emerges as a key determinant for subjecting an mRNA to NMD, and we therefore review recent structural and mechanistic insight into translation termination. In addition, the central role of UPF1, its crucial phosphorylation/dephosphorylation cycle and dynamic interactions with other NMD factors are discussed. Moreover, we address the role of exon junction complexes (EJCs) in NMD and summarize the functions of SMG5, SMG6 and SMG7 in promoting mRNA decay through different routes. This article is part of a Special Issue entitled: RNA Decay mechanisms. Copyright © 2013 Elsevier B.V. All rights reserved.

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A recessive skeletal dysplasia, SEMD aggrecan type, results from a missense mutation affecting the C-type lectin domain of aggrecan.

Stuart W J Tompson, Barry Merriman, Vincent Funari … (2009)

Analysis of a nuclear family with three affected offspring identified an autosomal-recessive form of spondyloepimetaphyseal dysplasia characterized by severe short stature and a unique constellation of radiographic findings. Homozygosity for a haplotype that was identical by descent between two of the affected individuals identified a locus for the disease gene within a 17.4 Mb interval on chromosome 15, a region containing 296 genes. These genes were assessed and ranked by cartilage selectivity with whole-genome microarray data, revealing only two genes, encoding aggrecan and chondroitin sulfate proteoglycan 4, that were selectively expressed in cartilage. Sequence analysis of aggrecan complementary DNA from an affected individual revealed homozygosity for a missense mutation (c.6799G --> A) that predicts a p.D2267N amino acid substitution in the C-type lectin domain within the G3 domain of aggrecan. The D2267 residue is predicted to coordinate binding of a calcium ion, which influences the conformational binding loops of the C-type lectin domain that mediate interactions with tenascins and other extracellular-matrix proteins. Expression of the normal and mutant G3 domains in mammalian cells showed that the mutation created a functional N-glycosylation site but did not adversely affect protein trafficking and secretion. Surface-plasmon-resonance studies showed that the mutation influenced the binding and kinetics of the interactions between the aggrecan G3 domain and tenascin-C. These findings identify an autosomal-recessive skeletal dysplasia and a significant role for the aggrecan C-type lectin domain in regulating endochondral ossification and, thereby, height.

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Author and article information

Contributors

Beth G. Gibson: beth.gibson@newcastle.ac.uk

Michael D. Briggs: michael.briggs@newcastle.ac.uk

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): 28 June 2016

Publication date PMC-release: 28 June 2016

Publication date Collection: 2016

Volume: 11

Electronic Location Identifier: 86

Affiliations

[ ]Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, NE1 3BZ UK

[ ]International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ UK

Article

Publisher ID: 459

DOI: 10.1186/s13023-016-0459-2

PMC ID: 4924316

PubMed ID: 27353333

SO-VID: e750dd7c-fe65-42f9-9cb6-d5ecf602a222

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 : 9 January 2016

Date accepted : 27 May 2016

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100004963, Seventh Framework Programme;

Award ID: 602300

Award Recipient : Michael D. Briggs

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ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: aggrecan,osteochondritis dissecans,chondrodysplasia,cartilage,skeletal dysplasia

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ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: aggrecan, osteochondritis dissecans, chondrodysplasia, cartilage, skeletal dysplasia

The aggrecanopathies; an evolving phenotypic spectrum of human genetic skeletal diseases

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Most cited references 34

Nosology and Classification of Genetic Skeletal Disorders: 2010 Revision

Nonsense-mediated mRNA decay - mechanisms of substrate mRNA recognition and degradation in mammalian cells.

A recessive skeletal dysplasia, SEMD aggrecan type, results from a missense mutation affecting the C-type lectin domain of aggrecan.

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