Abstract
Walker-Warburg syndrome, muscle-eye-brain disease, Fukuyama congenital muscular dystrophy, congenital muscular dystrophy type 1C, and congenital muscular dystrophy type 1D are overlapping clinical entities belonging to a subgroup of the congenital muscular dystrophies (CMD), collectively designated dystroglycanopathies, in which the common underlying defect is hypoglycosylation of alfa-dystroglycan. Currently, six different genes are known to be implicated in these diseases: POMT1, POMT2, POMGNT1, FCMD, FKRP, and LARGE. We report the molecular characterization of a patient presenting clinical features of CMD and reduced immunostaining for alfa-dystroglycan in muscle. Three candidate genes (FCMD, POMT1 and POMGNT1) were analyzed, and a total of 18 sequence variants were detected: 15 polymorphisms in POMT1 [including three unreported single nucleotide polymorphisms (SNPs)], two polymorphisms in FCMD, and the exonic silent mutation c.636C > T in POMGNT1. Expression analysis revealed that this apparently silent mutation compromises correct premessenger RNA (mRNA) splicing, promoting skipping of the entire exon 7, with a consequent frameshift. In silico analysis of this mutation did not predict alterations in the canonical splice sequences, but rather the creation of a new exonic splice silencer. The recognition of such disease-causing elements may contribute to the further understanding of RNA processing and assist mutation screening in routine diagnosis, where such changes may be underestimated. To aid clinical diagnosis, we generated publicly available LOVD-powered Locus Specific Databases for these three genes and recorded all known sequence variants (http://www.dmd.nl).
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Baralle D, Baralle M (2005) Splicing in action: assessing disease causing sequence changes. J Med Genet 42:737–748
Barresi R, Campbell KP (2006) Dystroglycan: from biosynthesis to pathogenesis of human disease. J Cell Sci 119:199–207
Beltran-Valero de Bernabe D, Currier S, Steinbrecher A, Celli J, van Beusekom E, van der Zwaag B, Kayserili H, Merlini L, Chitayat D, Dobyns WB, Cormand B, Lehesjoki AE, Cruces J, Voit T, Walsh CA, van Bokhoven H, Brunner HG (2002) Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. Am J Hum Genet 71:1033–1043
Brockington M, Blake DJ, Prandini P, Brown SC, Torelli S, Benson MA, Ponting CP, Estournet B, Romero NB, Mercuri E, Voit T, Sewry CA, Guicheney P, Muntoni F (2001) 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. Am J Hum Genet 69:1198–1209
Buratti E, Muro AF, Giombi M, Gherbassi D, Iaconcig A, Baralle FE (2004) RNA folding affects the recruitment of SR proteins by mouse and human polymorphic enhancer elements in the fibronectin EDA exon. Mol Cell Biol 24:1387–1400
Burge C, Karlin S (1997) Prediction of complete gene structures in human genomic. DNA J Mol Biol 268:78–94
Cartegni L, Chew SL, Krainer AR (2002) Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet 23:285–298
Cartegni L, Wang J, Zhu Z, Zhang MQ, Krainer AR (2003) ESEfinder: A web resource to identify exonic splicing enhancers. Nucleic Acids Res 31:3568–3571
Chen CD, Kobayashi R, Helfman DM (1999) Binding of hnRNP H to an exonic splicing silencer is involved in the regulation of alternative splicing of the rat beta-tropomyosin gene. Genes Dev 13:593–606
Cotton RG, Auerbach AD, Brown AF, Carrera P, Christodoulou J, Claustres M, Compton J, Cox DW, De Baere E, den Dunnen JT, Greenblatt M, Fujiwara M, Hilbert P, Jani A, Lehvaslaiho H, Nebert DW, Verma I, Vihinen M (2007) Recommendations of the 2006 Human Variome Project meeting. Nat Genet 39:433–436
den Dunnen JT, Antonarakis SE (2001) Nomenclature for the description of human sequence variations. Hum Genet 109:121–124
Diesen C, Saarinen A, Pihko H, Rosenlew C, Cormand B, Dobyns WB, Dieguez J, Valanne L, Joensuu T, Lehesjoki AE (2004) POMGnT1 mutation and phenotypic spectrum in muscle-eye-brain disease. J Med Genet 41:e115
Faustino NA, Cooper TA (2003) Pre-mRNA splicing and human disease. Genes Dev 17:419–437
Fokkema IF, den Dunnen JT, Taschner PE (2005) LOVD: easy creation of a locus-specific sequence variation database using an “LSDB-in-a-box” approach. Hum Mutat 26:63–68
Kobayashi K, Nakahori Y, Miyake M, Matsumura K, Kondo-Iida E, Nomura Y, Segawa M, Yoshioka M, Saito K, Osawa M, Hamano K, Sakakihara Y, Nonaka I, Nakagome Y, Kanazawa I, Nakamura Y, Tokunaga K, Toda T (1998a) An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 394:388–392
Liu J, Ball SL, Yang Y, Mei P, Zhang L, Shi H, Kaminski HJ, Lemmon VP, Hu H (2006) A genetic model for muscle-eye-brain disease in mice lacking protein O-mannose 1,2-N-acetylglucosaminyltransferase (POMGnT1). Mech Dev 123:228–240
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)). Methods 25:402–408
Longman C, Brockington M, Torelli S, Jimenez-Mallebrera C, Kennedy C, Khalil N, Feng L, Saran RK, Voit T, Merlini L, Sewry CA, Brown SC, Muntoni F (2003) Mutations in the human LARGE gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of alpha-dystroglycan. Hum Mol Genet 2(21):2853–2861
Martin PT (2006) Mechanisms of disease: congenital muscular dystrophies - glycosylation takes center stage. Nat Clin Pract Neurol 2:222–230
Mathews D, Sabina J, Zuker M, Turner DH (1999) Expanded sequence dependence of thermodynamic parameters improves prediction of RNA secondary structure. J Mol Biol 288:911–940
Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215
Pagani F, Stuani C, Tzetis M, Kanavakis E, Efthymiadou A, Doudounakis S, Casals T, Baralle FE (2003a) New type of disease causing mutations: the example of the composite exonic regulatory elements of splicing in CFTR exon 12. Hum Mol Genet 12:1111–1120
Pagani F, Buratti E, Stuani C, Baralle FE (2003b) Missense, nonsense and neutral mutations define juxtaposed regulatory elements of splicing in CFTR exon 9. J Biol Chem 278:26580–26588
Sironi M, Menozzi G, Riva L, Cagliani R, Comi GP, Bresolin N, Giorda R, Pozzoli U (2004) Silencer elements as possible inhibitors of pseudoexon splicing. Nucleic Acids Res 32:1783–1791
Taniguchi K, Kobayashi K, Saito K, Yamanouchi H, Ohnuma A, Hayashi YK, Manya H, Jin DK, Lee M, Parano E, Falsaperla R, Pavone P, Van Coster R, Talim B, Steinbrecher A, Straub V, Nishino I, Topaloglu H, Voit T, Endo T, Toda T (2003) Worldwide distribution and broader clinical spectrum of muscle-eye-brain disease. Hum Mol Genet 12:527–534
Uchikawa H, Fujii K, Kohno Y, Katsumata N, Nagao K, Yamada M, Miyashita T (2007) U7 snRNA-mediated correction of aberrant splicing caused by activation of cryptic splice sites. J Hum Genet 52:891–897
van Reeuwijk J, Janssen M, van den Elzen C, Beltran-Valero de Bernabe D, Sabatelli P, Merlini L, Boon M, Scheffer H, Brockington M, Muntoni F, Huynen MA, Verrips A, Walsh CA, Barth PG, Brunner HG, van Bokhoven H (2005) POMT2 mutations cause alpha-dystroglycan hypoglycosylation and Walker-Warburg syndrome. J Med Genet 42:907–912
Wang GS, Cooper TA (2007) Splicing in disease: disruption of the splicing code and the decoding machinery. Nat Rev Genet 8:749–761
Yoshida A, Kobayashi K, Manya H, Taniguchi K, Kano H, Mizuno M, Inazu T, Mitsuhashi H, Takahashi S, Takeuchi M, Herrmann R, Straub V, Talim B, Voit T, Topaloglu H, Toda T, Endo T (2001) Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1. Dev Cell 1:717–724
Zuker M (2003) Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res 31:26580–26588
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Oliveira, J., Soares-Silva, I., Fokkema, I. et al. Novel synonymous substitution in POMGNT1 promotes exon skipping in a patient with congenital muscular dystrophy. J Hum Genet 53, 565–572 (2008). https://doi.org/10.1007/s10038-008-0263-5
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1007/s10038-008-0263-5
Keywords
This article is cited by
-
Bi-allelic SMO variants in hypothalamic hamartoma: a recessive cause of Pallister-Hall syndrome
European Journal of Human Genetics (2022)
