FKRP gene mutations cause congenital muscular dystrophy, mental retardation, and cerebellar cysts

Background: Congenital muscular dystrophies (CMD) are autosomal recessive disorders that present within the first 6 months of life with hypotonia and a dystrophic muscle biopsy. CNS involvement is present in some forms. The fukutin-related protein gene (FKRP) is mutated in a severe form of CMD (MDC1C) and a milder limb girdle dystrophy (LGMD2I). Both forms have secondary deficiencies of laminin α2 and α-dystroglycan immunostaining. Structural brain involvement has not been observed in patients with FKRP gene mutations. Methods: The authors studied two unrelated patients who had a pattern of muscle involvement identical to MDC1C, mental retardation, and cerebellar cysts on cranial MRI. The FKRP gene was analyzed along with the skeletal muscle expression of laminin α2 and α-dystroglycan. Results: The muscle biopsy of both patients showed severe dystrophic findings, a reduction in laminin α2, and profound depletion of α-dystroglycan. Both patients had homozygous FKRP gene mutations not previously reported (C663A [Ser221Arg] and C981A [Pro315Thr]). Conclusions: Mutations within the FKRP gene can result in CMD associated with mental retardation and cerebellar cysts. This adds structural brain defects to the already wide spectrum of abnormalities caused by FKRP mutations. The severe depletion of α-dystroglycan expression suggests that FKRP is involved in the processing of α-dystroglycan.

[1]  I. Nonaka,et al.  Deficiency of α-Dystroglycan in Muscle–Eye–Brain Disease , 2002 .

[2]  F. Muntoni,et al.  85th ENMC International Workshop on Congenital Muscular Dystrophy 6th International CMD Workshop 1st Workshop of the Myo-Cluster Project ‘GENRE’27–28th October 2000, Naarden, The Netherlands , 2002, Neuromuscular Disorders.

[3]  Susan C. Brown,et al.  Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C. , 2001, Human molecular genetics.

[4]  Susan C. Brown,et al.  Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin alpha2 deficiency and abnormal glycosylation of alpha-dystroglycan. , 2001, American journal of human genetics.

[5]  M. Mizuno,et al.  Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1. , 2001, Developmental cell.

[6]  J. Guàrdia,et al.  1H-MR spectroscopy is sensitive to subtle effects of perinatal asphyxia , 2001, Neurology.

[7]  F. Muntoni,et al.  Mutations in SEPN1 cause congenital muscular dystrophy with spinal rigidity and restrictive respiratory syndrome , 2001, Nature Genetics.

[8]  I. Nonaka,et al.  Selective deficiency of α-dystroglycan in Fukuyama-type congenital muscular dystrophy , 2001, Neurology.

[9]  J. Hewitt,et al.  Mutant glycosyltransferase and altered glycosylation of α-dystroglycan in the myodystrophy mouse , 2001, Nature Genetics.

[10]  E. Bertini,et al.  Ullrich scleroatonic muscular dystrophy is caused by recessive mutations in collagen type VI , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[11]  A. Oto,et al.  Merosin-deficient congenital muscular dystrophy with mental retardation and cerebellar cysts unlinked to the LAMA2, FCMD and MEB loci , 2000, Neuromuscular Disorders.

[12]  Susan C. Brown,et al.  Congenital muscular dystrophy associated with calf hypertrophy, microcephaly and severe mental retardation in three Italian families: evidence for a novel CMD syndrome , 2000, Neuromuscular Disorders.

[13]  E. Mercuri,et al.  Congenital muscular dystrophy with secondary merosin deficiency and normal brain MRI: a novel entity? , 2000, Neuropediatrics.

[14]  F. Muntoni,et al.  Assignment of a form of congenital muscular dystrophy with secondary merosin deficiency to chromosome 1q42. , 2000, American journal of human genetics.

[15]  E. Koonin,et al.  The fukutin protein family – predicted enzymes modifying cell-surface molecules , 1999, Current Biology.

[16]  A. Imberty,et al.  Structure/function studies of glycosyltransferases. , 1999, Current opinion in structural biology.

[17]  I. Kanazawa,et al.  An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy , 1998, Nature.

[18]  F. Muntoni,et al.  Identification of a new locus for a peculiar form of congenital muscular dystrophy with early rigidity of the spine, on chromosome 1p35-36. , 1998, American journal of human genetics.

[19]  A. Helbling-Leclerc,et al.  Merosin-deficient congenital muscular dystrophy with severe mental retardation and normal cranial MRI: a report of two siblings , 1998, Neuromuscular Disorders.

[20]  E. Hoffman,et al.  Mutations in the integrin α7 gene cause congenital myopathy , 1998, Nature Genetics.

[21]  G. Carlson.  Proof of the primacy of prion protein , 1998, Nature Genetics.

[22]  J. Ervasti,et al.  Tissue-specific Heterogeneity in α-Dystroglycan Sialoglycosylation , 1997, The Journal of Biological Chemistry.

[23]  A. Paetau,et al.  Muscle—eye—brain disease: A neuropathological study , 1997, Annals of neurology.

[24]  I. Kanazawa,et al.  Structures of Sialylated O-Linked Oligosaccharides of Bovine Peripheral Nerve α-Dystroglycan , 1997, The Journal of Biological Chemistry.

[25]  J. Weissenbach,et al.  Mutations in the laminin α2–chain gene (LAMA2) cause merosin–deficient congenital muscular dystrophy , 1995, Nature Genetics.

[26]  N. Aida,et al.  Cerebellar MR in Fukuyama congenital muscular dystrophy: polymicrogyria with cystic lesions. , 1994, AJNR. American journal of neuroradiology.

[27]  K. Campbell,et al.  Congenital muscular dystrophy with merosin deficiency. , 1994, Comptes rendus de l'Academie des sciences. Serie III, Sciences de la vie.

[28]  V. Dubowitz.  22nd ENMC Sponsored Workshop on Congenital Muscular Dystrophy held in Baarn, The Netherlands, 14–16 May 1993 , 1994, Neuromuscular Disorders.

[29]  I. Nonaka,et al.  Deficiency of alpha-dystroglycan in muscle-eye-brain disease. , 2002, Biochemical and biophysical research communications.

[30]  T. Godwin,et al.  Congenital Muscular Dystrophy , 2015 .

[31]  A. Chapelle,et al.  Assignment of the muscle-eye-brain disease gene to 1p32-p34 by linkage analysis and homozygosity mapping. , 1999, American journal of human genetics.

[32]  J. Ervasti,et al.  Tissue-specific heterogeneity in alpha-dystroglycan sialoglycosylation. Skeletal muscle alpha-dystroglycan is a latent receptor for Vicia villosa agglutinin b4 masked by sialic acid modification. , 1997, The Journal of biological chemistry.

[33]  I. Kanazawa,et al.  Structures of sialylated O-linked oligosaccharides of bovine peripheral nerve alpha-dystroglycan. The role of a novel O-mannosyl-type oligosaccharide in the binding of alpha-dystroglycan with laminin. , 1997, The Journal of biological chemistry.