Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C

被引:354
作者
Brockington, M
Yuva, Y
Prandini, P
Brown, SC
Torelli, S
Benson, MA
Herrmann, R
Anderson, LVB
Bashir, R
Burgunder, JM
Fallet, S
Romero, N
Fardeau, M
Straub, V
Storey, G
Pollitt, C
Richard, I
Sewry, CA
Bushby, K
Voit, T
Blake, DJ
Muntoni, F
机构
[1] Univ London Imperial Coll Sci & Technol, Fac Med,Dubowitz Neuromuscular Ctr, Div Paediat Obstet & Gynaecol, Dubowtz Neuromuscular Unit,Dept Paediat, London W12 0NN, England
[2] Univ Cagliari, Dept Cytomorphol, I-09124 Cagliari, Italy
[3] Univ Oxford, Dept Human Anat & Genet, Oxford OX1 2JD, England
[4] Univ Essen Gesamthsch, Dept Paediat & Paediat Neurol, D-4300 Essen 1, Germany
[5] Univ Newcastle Upon Tyne, Dept Biochem & Genet, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England
[6] Univ Durham, Dept Biol Sci, Durham DH1 3HP, England
[7] Univ Bern, Inselspital, CH-3010 Bern, Switzerland
[8] Childrens Hosp New Jersey, Newark, NJ USA
[9] Grp Hosp Pitie Salpetriere, Inst Myol, INSERM, U523, F-75634 Paris, France
[10] Robert Jones & Agnes Hunt Orthopaed Hosp, Dept Histopathol, Oswestry SY10 7AG, Shrops, England
关键词
D O I
10.1093/hmg/10.25.2851
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The limb girdle and congenital muscular dystrophies (LGMD and CMD) are characterized by skeletal muscle weakness and dystrophic muscle changes. The onset of symptoms in CMD is within the first few months of life, whereas in LGMD they can occur in late childhood, adolescence or adult life. We have recently demonstrated that the fukutin-related protein gene (FKRP) is mutated in a severe form of CMD (MDC1C), characterized by the inability to walk, leg muscle hypertrophy and a secondary deficiency of laminin alpha2 and alpha -dystroglycan. Both MDC1C and LGMD2I map to an identical region on chromosome 19q13.3. To investigate whether these are allelic disorders, we undertook mutation analysis of FKRPin 25 potential LGMD2I families, including some with a severe and early onset phenotype. Mutations were identified in individuals from 17 families. A variable reduction of alpha -dystroglycan expression was observed in the skeletal muscle biopsy of all individuals studied. In addition, several cases showed a deficiency of laminin alpha2 either by immunocytochemistry or western blotting. Unexpectedly, affected individuals from 15 families had an identical C826A (Leu276Ileu) mutation, including five that were homozygous for this change. Linkage analysis identified at least two possible haplotypes in linkage disequilibrium with this mutation. Patients with the C826A change had the clinically less severe LGMD2I phenotype, suggesting that this is a less disruptive FKRP mutation than those found in MDC1C. The spectrum of LGMD2I phenotypes ranged from infants with an early presentation and a Duchenne-like disease course including cardiomyopathy, to milder phenotypes compatible with a favourable long-term outcome.
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页码:2851 / 2859
页数:9
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