Tag Archives: pseudoachondroplasia

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”

5 Things New Parents of Kids With Skeletal Dysplasia Need to Know

logoA very moving, but also informative blog from Mary Henderson who’s young daughter has pseudoachondroplasia. 

Please read the full article here, but here are Mary’s thoughts:-


Here’s what I think all new parents of children with skeletal dysplasias should know:

1. Every accomplishment — down to the smallest thing like learning how to step up a curb without help — will mean the world to you. You will feel a pride many other parents are not lucky enough to know. You will take nothing for granted, and celebrate every success of your child. Your highs might be higher and lows lower than others. Hold onto those highs and keep them close to your heart.

2. You will find many along a similar journey and many to support you, but all our journeys are unique. You will learn how you want to handle your own situations and how to teach your own child. I am not comfortable referring to my daughter as a “little person,” though so many with a form of dwarfism are OK with it. I choose not to label my daughter in any way, and I respect those who choose to use that term or others. You choose your journey and respect other journeys.

3. Your child’s diagnosis and this new journey you are on will make you a better person; this I promise you. I could not even see far enough down my black tunnel a few years ago to understand this, but I am learning. I have a long way to go, but I do know that in a few quick years I am a stronger, more tolerant, understanding, compassionate, giving and kind person than I ever was. I have a hard time believing the “I was given this child for a reason” scenario, but sometimes I do have to wonder if there’s some truth to it.

4. You will become ultra sensitive to all discussions/comments regarding size, whether it’s about being very tall or very short. People say things — lots of thing without even thinking twice — and you have to take it with a grain of salt. I’d spend my days sad and angry and hurt if I let everyone’s comments (not even about my daughter) get to me. Yes, they do sometimes, especially if coming from people I care about, but I do my best to move on. Know that most people don’t mean anything by it and you likely wouldn’t have thought twice about commenting on size or growth if you weren’t in this boat. Speak up when you choose to — pick your battles.

5. Read and take comfort in the famous “Welcome to Holland” story by Emily Perl Kingsley. I know it saved me in my darkest hour many times. It’s something many people will never be privy to if they are not given a reason to read it. I cannot recall who exactly sent it to me, but I do know I’ve read it time and again, and it is very special and so true. It takes time to believe. You will have many moments where you wish you had the trip to Italy, but in time you will understand that Holland really is much better.

Please visit Mary’s site and help if you can.

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.

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