Tag Archives: Multiple epiphyseal dysplasia

Armet/Manf as a potential secreted biomarker for ER stress related diseases


Recent article published by Dr Chen and colleagues confirming that Armlet/Manf can potentially act as a diagnostic and/or prognostic biomarker in ER stress–related kidney diseases. This will help to stratify disease risk, predict disease progression, monitor treatment response and possible identify subgroups of patients who can be treated with ER stress modulators in a highly targeted manner.

This finding supports our 2103 paper using mouse models of genetic skeletal diseases Harley 2013

In this study we hypothesised that:-

“The interesting observation that Armet and Creld2 are secreted under conditions of increased ER stress suggests the possibility that they may be exploited as soluble extracellular biomarkers of ER stress-related diseases that are gene product and/or mutation specific”

Recurrent COMP missense mutations

What are their prevalence and significance?

(No easy answer, but…………)EJHG 2014Having recently complied a comprehensive list of COMP mutations from 300 case studies published over the last 18 years (see here or download ejhg201430a) we set out to identify recurrent COMP mutations and determine their geographical/ethnic distribution.

Here are our “Top 6”  COMP mutations with the total number [n=] of reported cases :-

  • c.925G> p.(Gly309Arg) [n=4]
  • c.1153G>A p.(Asp385Asn) [n=13]
  • c.1318G>A p.(Gly440Arg) [n=7]
  • c.1552G>A p.(Asp518Asn) [n=4]
  • c.1569C>G p.(Asn523Lys) [n=4]
  • c.2152C>T p.(Arg718Trp) [n=8]

It is clear from this list that p.Asp385Asn is by far the most prevalent missense mutation and deserves further investigation.

Here are the details of all 13 individual cases reported in the literature:-

MED c.1153G>A p.(Asp385Asn) Kim et al AJMG 2011
MED c.1153G>A p.(Asp385Asn) Kim et al AJMG 2011
MED c.1153G>A p.(Asp385Asn) Kim et al AJMG 2011
MED c.1153G>A p.(Asp385Asn) Kim et al AJMG 2011
MED c.1153G>A p.(Asp385Asn) Song et al J Hum Genet 2003
MED c.1153G>A p.(Asp385Asn) Mabuchi et al Hum Genet 2003
MED c.1153G>A p.(Asp385Asn) Kennedy et al EJHG 2005
MED c.1153G>A p.(Asp385Asn) Kennedy et al EJHG 2005
MED c.1153G>A p.(Asp385Asn) Kennedy et al EJHG 2005
MED c.1153G>A p.(Asp385Asn) Kennedy et al EJHG 2005
MED non typical c.1153G>A p.(Asp385Asn) Jackson et al Hum Mut 2012
MED c.1153G>A p.(Asp385Asn) Jackson et al Hum Mut 2012
MED c.1153G>A p.(Asp385Asn) Jackson et al Hum Mut 2012

Points to note:-

  1. All individuals have the same nucleotide transition at c.1153G>A.
  2. The mutation appears equally in Asian (Kim, Song & Mabuchi)  and European (Kennedy & Jackson) studies suggesting increased prevalence is probably not due to a founder affect.
  3. Analysis of the Kennedy and Jackson studies confirms individuals are located throughout Europe [Switzerland n=1, The Netherlands n=2 and UK n=5] but it remains possible that there is a founder effect in the UK.
  4. Interestingly, a varient at the neighbouring reside (p.Asn386Asp) is one of the few confirmed and non-disease causing polymorphisms in COMP.

Clinical symptoms of MED patients caused by MATN3 and COMP gene mutations

Interesting paper from the group in Korea……BMC article

The medical records and radiographs of 59 molecularly confirmed multiple epiphyseal dysplasia (MED) patients were reviewed along with questionnaire surveys or telephone interviews.

Several very interesting and important correlations were identified:-

  • There appeared to be no difference in age of onset of symptoms; 8 years for both COMP and MATN3 mutations.
  • MED patients with COMP mutations were significantly shorter.
  • Hip pain and limitation of daily activity were more frequent in MED patients with COMP mutations.
  • Clinical symptoms of MED caused by MATN3 mutations were milder that the symptoms of COMP mutations.

And importantly………

“These differences in clinical manifestation and prognosis justify molecular differentiation between the two genotypes”.

The full article can be downloaded here 1471-2474-15-84

Rare disease talks at MBE 2014 in Rotterdam this week

MBE 2014

Looking forward to some rare disease talks at 1st MBE (Matrix Biology Europe) conference (XXIVth FECTS meeting) 21 – 24 June 2014


New insights in collagen processing as revealed by autosomal recessive forms of osteogenesis imperfecta (Joan Marini – Bethesda)

Defective proteolytic processing of fibrillar procollagens and other extracellular matrix proteins due to mutations in BMP1 result in a severe form of osteogenesis imperfecta (Delfien Syx – Ghent)

Skeletal dysplasias and the molecular pathology of the unfolded protein response (John Bateman – Melbourne)

ECM mutations in multiple epiphyseal dysplasias and pseudoachondrodysplasia (Michael Briggs – Newcastle)

The effect of fibrillin mutations: Altered TGF-beta and heparin binding results in a variety of connective tissue diseases (Cay Kielty – Manchester)

Mesenchymal stromal cell therapy for recessive dystrophic epidermolysis bullosa (Tobias Kühl – Freiburg)

Nonsense-mediated mRNA decay of collagen – emerging complexity in RNA surveillance mechanisms (Shireen Lamandé – Melbourne)

Basement membranes and human disease (Leena Bruckner-Tuderman – Freiburg)

HANAC Col4A1 mutation in mice causes a muscular disease with endoplamic reticulum stress and vascular defects (Emmanuelle Plaisier – Paris)

Chemical chaperone treatment to target haemorrhagic stroke caused by collagen IV mutations (Tom Van Agtmael – Glasgow)

Full Programme here 2. 1st MBE Conference 2014 Program

Gene identification in rare skeletal diseases

An interesting historical breakdown of gene identification for rare skeletal diseases in the 25 years from 1988 to 2011.

GSD gene identification

What becomes apparent is that technology clearly drives the process of gene discovery and that there are ‘peaks in discovery’ that are closely aligned with ‘new’ technologies.

  • The availability of highly informative microsatelllite markers, which could even be assembled into panels for multiplexing (pioneered by Jim Weber in Marshfield Wisconsin), heralded the first increase in gene identification starting in the early to mid 1990’s.
  • This approach was massively enhanced with the publication of the Human Genome, which allowed a rapid transition from candidate region to candidate genes. For example, in our multiple epiphyseal dysplasia (MED) study of 2001 we went from a linked candidate region of 60cM to three candidate genes; TIMP3, SDC1 and MATN3 – we chose wisely  Chapman et al 01.
  • High throughput SNP analysis aided in the identification of numerous genes responsible for recessive skeletal diseases through homozygosity mapping.
  • Most recently arrays and next generation sequencing has completely revolutionised disease gene discovery in rare (skeletal) diseases.



A super example of gene discovery using exome sequencing comes from Andreas Zankl, Matt Brown and colleagues.

In summary, exome sequencing of both parents and the affected siblings in this family identified:-

  • 90% of targeted nucleotides had coverage of >four-fold
  • 79% of targeted nucleotides had coverage >ten-fold
  • ~15,000 SNPs identified following bioinformatic filtering!


  • >96% SNPs were reported in the recent dbSNP database and were therefore excluded from further analysis as unlikely to cause this rare disease.
  • Following the functional annotation of the remaining novel SNPs, focused analyses on a set of 483 unique novel coding non-synonymous SNPs that were detected in at least one sample.
  • Careful selection of ‘mode of inheritance’ allowed the identification of just four candidate genes.
  • In all but one gene the detected missense mutations were predicted to be tolerated in terms of effect upon protein function.

The single remaining candidate gene carried two novel alleles :-

  • One creating a premature stop codon.
  • One causing a missense mutation predicted to have a damaging effect on protein function.
  • POP1 a strong candidate for the disease-causing gene in this family.

Needless to say that this story made a great 2nd year undergraduate lecture Exome Lecture.