Molecular Analysis Confirms that FKRP-Related Disorders are Underdiagnosed in Mexican Patients with Neuromuscular Diseases

Abstract

The FKRP-related disorders include the limb-girdle muscular dystrophy type 2I (LGMD2I, MIM#607155) which has a clinical overlap with dystrophinopathies. Except for Brazil, LGMD2I has not been described in other Latin-American countries, despite that 1/64 Mexican-ancestry individuals carry the commonest European p.(Leu276Ile) pathogenic FKRP variant (rs28937900, 1000 Genomes Project Phase 3), suggesting an underdiagnosis. Sequencing of exon 4 of FKRP in 60 unrelated Mexican patients with presumptive diagnoses of dystrophinopathy without DMD gene deletions, or with a neuromuscular disorder of unknown etiology, revealed two patients (2/60, 3.3%): one of them with an unreported pathogenic genotype, p.[Leu276Ile];[Asn463Asp] and a Duchenne-like phenotype; and the other that stands as the third reported case bearing the severe genotype, p.[Asn463Asp];[Asn463Asp] leading to a congenital presentation (MIM#606612). We identified two patients heterozygous for the p.(Arg143Ser) and the novel p.(Arg48Pro) variants, respectively, which were absent in 200 control alleles. Protein modeling suggests that p.(Arg143Ser) is a tolerated change, while p.(Arg48Pro) induces a structural modification, although further molecular confirmation of dystrophinopathy was obtained in the p.(Arg48Pro) patient. Our results justify the inclusion of FKRP-related disorders in the differential diagnosis of Mexican neuromuscular patients. The commonly reported heterozygous FKRP genotypes deserve attention to avoid LGMD2I molecular misdiagnosis.

Keywords

α-dystroglycanopathies - Duchenne and Becker muscular dystrophies - fukutin-related protein - protein modeling - variants of uncertain significance

• References

• 1 Poppe M, Cree L, Bourke J. , et al. The phenotype of limb-girdle muscular dystrophy type 2I. Neurology 2003; 60 (08) 1246-1251
• 2 Mercuri E, Brockington M, Straub V. , et al. Phenotypic spectrum associated with mutations in the fukutin-related protein gene. Ann Neurol 2003; 53 (04) 537-542
• 3 Sveen ML, Schwartz M, Vissing J. High prevalence and phenotype-genotype correlations of limb girdle muscular dystrophy type 2I in Denmark. Ann Neurol 2006; 59 (05) 808-815
• 4 Schwartz M, Hertz JM, Sveen ML, Vissing J. LGMD2I presenting with a characteristic Duchenne or Becker muscular dystrophy phenotype. Neurology 2005; 64 (09) 1635-1637
• 5 Fu X, Yang H, Wei C. , et al. FKRP mutations, including a founder mutation, cause phenotype variability in Chinese patients with dystroglycanopathies. J Hum Genet 2016; 61 (12) 1013-1020
• 6 Brockington M, Yuva Y, Prandini P. , 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. Hum Mol Genet 2001; 10 (25) 2851-2859
• 7 Walter MC, Petersen JA, Stucka R. , et al. FKRP (826C>A) frequently causes limb-girdle muscular dystrophy in German patients. J Med Genet 2004; 41 (04) e50
• 8 Frosk P, Greenberg CR, Tennese AA. , et al. The most common mutation in FKRP causing limb girdle muscular dystrophy type 2I (LGMD2I) may have occurred only once and is present in Hutterites and other populations. Hum Mutat 2005; 25 (01) 38-44
• 9 de Paula F, Vieira N, Starling A. , et al. Asymptomatic carriers for homozygous novel mutations in the FKRP gene: the other end of the spectrum. Eur J Hum Genet 2003; 11 (12) 923-930
• 10 Gómez-Díaz B, Rosas-Vargas H, Roque-Ramírez B. , et al. Immunodetection analysis of muscular dystrophies in Mexico. Muscle Nerve 2012; 45 (03) 338-345
• 11 Bermúdez-López C, García-de Teresa B, González-del Angel A, Alcántara-Ortigoza MA. Germinal mosaicism in a sample of families with Duchenne/Becker muscular dystrophy with partial deletions in the DMD gene. Genet Test Mol Biomarkers 2014; 18 (02) 93-97
• 12 Richards S, Aziz N, Bale S. , et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17 (05) 405-424
• 13 Fischer D, Walter MC, Kesper K. , et al. Diagnostic value of muscle MRI in differentiating LGMD2I from other LGMDs. J Neurol 2005; 252 (05) 538-547
• 14 MacLeod H, Pytel P, Wollmann R. , et al. A novel FKRP mutation in congenital muscular dystrophy disrupts the dystrophin glycoprotein complex. Neuromuscul Disord 2007; 17 (04) 285-289
• 15 Boito CA, Melacini P, Vianello A. , et al. Clinical and molecular characterization of patients with limb-girdle muscular dystrophy type 2I. Arch Neurol 2005; 62 (12) 1894-1899
• 16 Fernandez C, de Paula AM, Figarella-Branger D. , et al. Diagnostic evaluation of clinically normal subjects with chronic hyperCKemia. Neurology 2006; 66 (10) 1585-1587
• 17 Guglieri M, Magri F, D'Angelo MG. , et al. Clinical, molecular, and protein correlations in a large sample of genetically diagnosed Italian limb girdle muscular dystrophy patients. Hum Mutat 2008; 29 (02) 258-266
• 18 Fanin M, Nascimbeni AC, Aurino S. , et al. Frequency of LGMD gene mutations in Italian patients with distinct clinical phenotypes. Neurology 2009; 72 (16) 1432-1435
• 19 Magri F, Del Bo R, D'Angelo MG. , et al. Frequency and characterisation of anoctamin 5 mutations in a cohort of Italian limb-girdle muscular dystrophy patients. Neuromuscul Disord 2012; 22 (11) 934-943
• 20 Stehlíková K, Skálová D, Zídková J. , et al. Autosomal recessive limb-girdle muscular dystrophies in the Czech Republic. BMC Neurol 2014; 14: 154
• 21 Hanisch F, Grimm D, Zierz S, Deschauer M. Frequency of the FKRP mutation c.826C>A in isolated hyperCKemia and in limb girdle muscular dystrophy type 2 in German patients. J Neurol 2010; 257 (02) 300-301
• 22 Bourteel H, Vermersch P, Cuisset JM. , et al. Clinical and mutational spectrum of limb-girdle muscular dystrophy type 2I in 11 French patients. J Neurol Neurosurg Psychiatry 2009; 80 (12) 1405-1408
• 23 Stensland E, Lindal S, Jonsrud C. , et al. Prevalence, mutation spectrum and phenotypic variability in Norwegian patients with limb girdle muscular dystrophy 2I. Neuromuscul Disord 2011; 21 (01) 41-46
• 24 Vieira NM, Schlesinger D, de Paula F, Vainzof M, Zatz M. Mutation analysis in the FKRP gene provides an explanation for a rare cause of intrafamilial clinical variability in LGMD2I. Neuromuscul Disord 2006; 16 (12) 870-873
• 25 Schottlaender LV, Petzold A, Wood N, Houlden H. Diagnostic clues and manifesting carriers in fukutin-related protein (FKRP) limb-girdle muscular dystrophy. J Neurol Sci 2015; 348 (1-2): 266-268
• 26 Yamamoto LU, Velloso FJ, Lima BL. , et al. Muscle protein alterations in LGMD2I patients with different mutations in the Fukutin-related protein gene. J Histochem Cytochem 2008; 56 (11) 995-1001
• 27 Alhamidi M, Kjeldsen Buvang E, Fagerheim T. , et al. Fukutin-related protein resides in the Golgi cisternae of skeletal muscle fibres and forms disulfide-linked homodimers via an N-terminal interaction. PLoS One 2011; 6 (08) e22968
• 28 Krag TO, Vissing J. A new mouse model of limb-girdle muscular dystrophy type 2I homozygous for the common L276I mutation mimicking the mild phenotype in humans. J Neuropathol Exp Neurol 2015; 74 (12) 1137-1146