Exome sequencing identifies titin mutations causing hereditary myopathy with early respiratory failure (HMERF) in families of diverse ethnic origins.

BMC Neurol 2013 Mar 20;13:29. Epub 2013 Mar 20.

Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

Background: Hereditary myopathy with early respiratory failure (HMERF) was described in several North European families and recently linked to a titin gene (TTN) mutation. We independently studied HMERF-like diseases with the purpose to identify the cause, refine diagnostic criteria, and estimate the frequency of this disease among myopathy patients of various ethnic origins.

Methods: Whole exome sequencing analysis was carried out in a large U.S. family that included seven members suffering from skeletal muscle weakness and respiratory failure. Subsequent mutation screening was performed in further 45 unrelated probands with similar phenotypes. Studies included muscle strength evaluation, nerve conduction studies and concentric needle EMG, respiratory function test, cardiologic examination, and muscle biopsy.

Results: A novel TTN p.Gly30150Asp mutation was identified in the highly conserved A-band of titin that co-segregated with the disease in the U.S. family. Screening of 45 probands initially diagnosed as myofibrillar myopathy (MFM) but excluded based on molecular screening for the known MFM genes led to the identification of a previously reported TTN p.Cys30071Arg mutation in one patient. This same mutation was also identified in a patient with suspected HMERF. The p.Gly30150Asp and p.Cys30071Arg mutations are localized to a side chain of fibronectin type III element A150 of the 10th C-zone super-repeat of titin.

Conclusions: Missense mutations in TTN are the cause of HMERF in families of diverse origins. A comparison of phenotypic features of HMERF caused by the three known TTN mutations in various populations allowed to emphasize distinct clinical/pathological features that can serve as the basis for diagnosis. The newly identified p.Gly30150Asp and the p.Cys30071Arg mutation are localized to a side chain of fibronectin type III element A150 of the 10th C-zone super-repeat of titin.

Download full-text PDF

Source
http://bmcneurol.biomedcentral.com/articles/10.1186/1471-237
Publisher Site
http://dx.doi.org/10.1186/1471-2377-13-29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3610280PMC
March 2013
32 Reads

Publication Analysis

Top Keywords

respiratory failure
12
failure hmerf
8
element a150
8
mutation identified
8
myopathy early
8
pgly30150asp pcys30071arg
8
hmerf families
8
side chain
8
type iii
8
c-zone super-repeat
8
chain fibronectin
8
families diverse
8
hereditary myopathy
8
early respiratory
8
fibronectin type
8
pcys30071arg mutation
8
iii element
8
localized side
8
exome sequencing
8
a150 10th
8

References

(Supplied by CrossRef)

L Edström et al.
J Neurol Sci 1990

PF Chinnery et al.
Ann Neurol 2001

D Birchall et al.
Neuromuscul Disord 2005

G Tasca et al.
Neuromuscul Disord 2010

S Lange et al.
Science 2005

O Mayans et al.
Nature 1998

G Pfeffer et al.
Brain 2012

M Ohlsson et al.
Brain 2012

B Gerull et al.
Nat Genet 2002

P Hackman et al.
Am J Hum Genet 2002

H Haravuori et al.
Neurology 2001

Similar Publications