Variable disease severity in Saudi Arabian and Sudanese families with c.3924 + 2 T > C mutation of LAMA2

BMC Research Notes

Marina Mora⁵  Lucia Morandi⁵  Renato Mantegazza⁵  Kevin P Campbell⁷  Christopher A Walsh²  Zein A Karrar⁶  Maowia M Mukhtar¹  Mohammed Z Seidahmed⁸  Steven A Moore⁴  M Chiara Manzini²  Mustafa AM Salih³  Emanuela Bellafiore⁵  Claudia Di Blasi⁵ 

[1] Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan;Howard Hughes Medical Institute, Division of Genetics and Manton Center for Orphan Disease Research, Children's Hospital, Boston, MA 02115, USA;Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia;Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA;Division of Neuromuscular Diseases and Neuroimmunology, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy;Department of Pediatrics and Child Health, College of Medicine, University of Khartoum, Khartoum, Sudan;Howard Hughes Medical Institute and Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA;Department of Pediatrics, Security Forces Hospital, Riyadh, Saudi Arabia

关键词: Merosin;    Laminin α2 chain;    gene;    LAMA2;    MDC1A;   

Others  :  1166886
DOI  :  10.1186/1756-0500-4-534

 received in 2011-10-20, accepted in 2011-12-13,  发布年份 2011

【 摘 要 】

Background

Congenital muscular dystrophy type 1A is caused by mutations in the LAMA2 gene that encodes the laminin α2 chain, a component of the skeletal muscle extracellular matrix protein laminin-211. The clinical spectrum of the disease is more heterogeneous than previously thought, particularly in terms of motor achievement and disease progression. We investigated clinical findings and performed molecular genetic analysis in 3 families from Saudi Arabia and 1 from Sudan in whom congenital muscular dystrophy 1A was suspected based on homozygosity mapping and laminin α2 chain deficiency.

Methods

We investigated 9 affected individuals from 1 Sudanese and 3 Saudi families in whom MDC1A was suggested by clinical, neuroimaging and/or pathological findings and by homozygosity mapping at the LAMA2 locus. Morphological and immunohistochemical analysis were performed in 3 patients from the 3 Saudi families. SSCP analysis, DNA sequencing and microsatellite analysis were carried out in the 4 index cases.

Results

A previously described mutation in the LAMA2 gene, a homozygous T > C substitution at position +2 of the consensus donor splice site of exon 26, was found in the 4 index patients. Clinical evaluation of 9 patients from the 4 families revealed variable disease severity particularly as regards motor achievement and disease progression. Microsatellite analysis showed an identical mutation-associated haplotype in the 4 index cases indicating a founder effect of the mutation in all 4 families.

Conclusions

Our data provide further evidence that the clinical spectrum of MDC1A due to a single mutation is heterogeneous, particularly in terms of motor achievement and disease progression, making it difficult to give a reliable prognosis even in patients with identical LAMA2-associated haplotype. The c.3924 + 2 T > C mutation to date has been found only in patients originating from the Middle East or Sudan; therefore laminin 2 chain deficiency in patients from those regions should initially prompt a search for this mutation.

【 授权许可】

   
2011 Mora et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Helbling-Leclerc A, Zhang X, Topaloglu H, Cruaud C, Tesson F, Weissenbach J, Tomé FM, Schwartz K, Fardeau M, Tryggvason K, et al.: Mutations in the laminin alpha 2-chain gene (LAMA2) cause merosin-deficient congenital muscular dystrophy. Nat Genet 1995, 11(2):216-218.
• [2]Aumailley M, Bruckner-Tuderman L, Carter WG, Deutzmann R, Edgar D, Ekblom P, Engel J, Engvall E, Hohenester E, Jones JC, et al.: A simplified laminin nomenclature. Matrix Biol 2005, 24(5):326-332.
• [3]Leivo I, Engvall E: Merosin, a protein specific for basement membranes of Schwann cells, striated muscle, and trophoblast, is expressed late in nerve and muscle development. Proc Natl Acad Sci USA 1988, 85(5):1544-1548.
• [4]Tomé FM, Evangelista T, Leclerc A, Sunada Y, Manole E, Estournet B, Barois A, Campbell KP, Fardeau M: Congenital muscular dystrophy with merosin deficiency. C R Acad Sci III 1994, 317(4):351-357.
• [5]Dubowitz V, Fardeau M: Proceedings of the 27th ENMC sponsored workshop on congenital muscular dystrophy. 22-24 April 1994, The Netherlands. Neuromuscul Disord 1995, 5(3):253-258.
• [6]Philpot J, Sewry C, Pennock J, Dubowitz V: Clinical phenotype in congenital muscular dystrophy: correlation with expression of merosin in skeletal muscle. Neuromuscul Disord 1995, 5(4):301-305.
• [7]Geranmayeh F, Clement E, Feng LH, Sewry C, Pagan J, Mein R, Abbs S, Brueton L, Childs AM, Jungbluth H, et al.: Genotype-phenotype correlation in a large population of muscular dystrophy patients with LAMA2 mutations. Neuromuscul Disord 2010, 20(4):241-50.
• [8]Pegoraro E, Fanin M, Trevisan CP, Angelini C, Hoffman EP: A novel laminin alpha2 isoform in severe laminin alpha2 deficient congenital muscular dystrophy. Neurology 2000, 55(8):1128-1134.
• [9]Prandini P, Berardinelli A, Fanin M, Morello F, Zardini E, Pichiecchio A, Uggetti C, Lanzi G, Angelini C, Pegoraro E: LAMA2 loss-of-function mutation in a girl with a mild congenital muscular dystrophy. Neurology 2004, 63(6):1118-1121.
• [10]Di Blasi C, Piga D, Brioschi P, Moroni I, Pini A, Ruggieri A, Zanotti S, Uziel G, Jarre L, Della Giustina E, et al.: LAMA2 gene analysis in congenital muscular dystrophy: new mutations, prenatal diagnosis, and founder effect. Arch Neurol 2005, 62(10):1582-1586.
• [11]Vigliano P, Dassi P, Di Blasi C, Mora M, Jarre L: LAMA2 stop-codon mutation: Merosin-deficient congenital muscular dystrophy with occipital polymicrogyria, epilepsy and psychomotor regression. Eur J Paediatr Neurol 2009, 13(1):72-76.
• [12]Allamand V, Sunada Y, Salih MA, Straub V, Ozo CO, Al-Turaiki MH, Akbar M, Kolo T, Colognato H, Zhang X, et al.: Mild congenital muscular dystrophy in two patients with an internally deleted laminin alpha2-chain. Hum Mol Genet 1997, 6(5):747-752.
• [13]Dib C, Fauré S, Fizames C, Samson D, Drouot N, Vignal A, Millasseau P, Marc S, Hazan J, Seboun E, et al.: A comprehensive genetic map of the human genome based on 5264 microsatellites. Nature 1996, 380(6570):152-154.
• [14]Guicheney P, Vignier N, Zhang X, He Y, Cruaud C, Frey V, Helbling-Leclerc A, Richard P, Estournet B, Merlini L, et al.: PCR based mutation screening of the laminin alpha2 chain gene (LAMA2): application to prenatal diagnosis and search for founder effects in congenital muscular dystrophy. J Med Genet 1998, 35(3):211-217.
• [15]Di Blasi C, He Y, Morandi L, Cornelio F, Guicheney P, Mora M: Mild muscular dystrophy due to a nonsense mutation in the LAMA2 gene resulting in exon skipping. Brain 2001, 124(Pt 4):698-704.
• [16]Siala O, Kammoun Feki F, Louhichi N, Hadj Salem I, Gribaa M, Elghzel H, Saad A, Triki C, Fakhfakh F: Molecular prenatal diagnosis of muscular dystrophies in Tunisia and postnatal follow-up role. Genet Test 2008, 12(4):581-586.
• [17]Heydemann A, Doherty KR, McNally EM: Genetic modifiers of muscular dystrophy: implications for therapy. Biochim Biophys Acta 2007, 1772(2):216-228.
• [18]Salih MA, Omer MI, Bayoumi RA, Karrar O, Johnson M: Severe autosomal recessive muscular dystrophy in an extended Sudanese kindred. Dev Med Child Neurol 1983, 25(1):43-52.
• [19]Salih MA: Childhood muscular dystrophy: an African review. Ann Trop Paediatr 1985, 5(4):167-173.
• [20]Salih MA, Mahdi AH, al-Jarallah AA, al Jarallah AS, al-Saadi M, Hafeez MA, Aziz SA: Childhood neuromuscular disorders: a decade's experience in Saudi Arabia. Ann Trop Paediatr 1996, 16(4):271-280.
• [21]Salih MA, Mahdi AH, al-Rikabi AC, al-Bunyan M, Roberds SL, Anderson RD, Campbell KP: Clinical and molecular pathological features of severe childhood autosomal recessive muscular dystrophy in Saudi Arabia. Dev Med Child Neurol 1996, 38(3):262-270.
• [22]Salih MAM: Muscular dystrophies and myopathies in Arab populations. In Genetic Disorders among Arab Populations. 2nd edition. Edited by Teebi AS. Berlin Heidelberg: Springer-Verlag; 2010:145-179.