Clinical, genetic, and pathologic characterization of FKRP Mexican founder mutation c.1387A>G

Abstract

ObjectiveTo characterize the clinical phenotype, genetic origin, and muscle pathology of patients with the FKRP c.1387A>G mutation.MethodsStandardized clinical data were collected for all patients known to the authors with c.1387A>G mutations in FKRP. Muscle biopsies were reviewed and used for histopathology, immunostaining, Western blotting, and DNA extraction. Genetic analysis was performed on extracted DNA.ResultsWe report the clinical phenotypes of 6 patients homozygous for the c.1387A>G mutation in FKRP. Onset of symptoms was <2 years, and 5 of the 6 patients never learned to walk. Brain MRIs were normal. Cognition was normal to mildly impaired. Microarray analysis of 5 homozygous FKRP c.1387A>G patients revealed a 500-kb region of shared homozygosity at 19q13.32, including FKRP. All 4 muscle biopsies available for review showed end-stage dystrophic pathology, near absence of glycosylated α-dystroglycan (α-DG) by immunofluorescence, and reduced molecular weight of α-DG compared with controls and patients with homozygous FKRP c.826C>A limb-girdle muscular dystrophy.ConclusionsThe clinical features and muscle pathology in these newly reported patients homozygous for FKRP c.1387A>G confirm that this mutation causes congenital muscular dystrophy. The clinical severity might be explained by the greater reduction in α-DG glycosylation compared with that seen with the c.826C>A mutation. The shared region of homozygosity at 19q13.32 indicates that FKRP c.1387A>G is a founder mutation with an estimated age of 60 generations (∼1,200–1,500 years).

Predominance of Dystrophinopathy Genotypes in Mexican Male Patients Presenting as Muscular Dystrophy with A Normal Multiplex Polymerase Chain Reaction DMD Gene Result: A Study Including Targeted Next-Generation Sequencing

“…We did not identify the founder LGMD2A or R1-causing CAPN3 pathogenic variant, c.384C > A or p.(Ala116Asp), or the non-founder micro indel CAPN3 mutation described in patients belonging to an endogamic region of Tlaxcala, Mexico [11]. The previously reported FKRP p.[Leu276Ile];[Asn463Asp] heterozygous compound genotype, which to date has been described only in LGMD2I patients of Mexican/Hispanic descent [13,18,19], was herein identified in one non-consanguineous LMGD family (DMD-786), which remarkably was referred with two affected siblings that died during the second and third decade of life; this was attributed to dilated cardiomyopathy, which was corroborated by autopsy in DMD-786. Although cardiomyopathy and other cardiac disturbances are expected in half of LGMD2I or R9 patients [4], dilated cardiomyopathy was not previously described in the five reported Mexican/Hispanic patients bearing the p.[Leu276Ile];[Asn463Asp] FKRP genotype [13,19].…”

“…The previously reported FKRP p.[Leu276Ile];[Asn463Asp] heterozygous compound genotype, which to date has been described only in LGMD2I patients of Mexican/Hispanic descent [13,18,19], was herein identified in one non-consanguineous LMGD family (DMD-786), which remarkably was referred with two affected siblings that died during the second and third decade of life; this was attributed to dilated cardiomyopathy, which was corroborated by autopsy in DMD-786. Although cardiomyopathy and other cardiac disturbances are expected in half of LGMD2I or R9 patients [4], dilated cardiomyopathy was not previously described in the five reported Mexican/Hispanic patients bearing the p.[Leu276Ile];[Asn463Asp] FKRP genotype [13,19]. However, decreased ejection fractions on echocardiogram were noted for two of these patients (at 21 and 22 years of age) [19], suggesting that the cardiological phenotype for patients with this compound heterozygous FKRP genotype has not yet been fully delineated.…”

“…NGS for DMD and the LGMD-related genes was performed by Admera Health (NJ, USA, ). The LGMD genes were selected based on their frequencies identified by immunoanalysis of muscle biopsies from Mexican patients with suspected muscular dystrophies ( CAPN3, DYSF, SGCG, SGCB, SGCA, SGCD and CAV3 ) [12], evidence for a founder effect in our population ( CAPN3 [11] and FKRP [13,18,19]), difficulties performing immunological assessment of the encoded protein in muscle biopsies ( ANO5, CAPN3 and FKRP ) [4,12], inaccuracy in the results of the immunological assessment ( CAPN3 ) [20] or evident overlap of clinical manifestations with DMD/BMD, such as the predominance of childhood onset for proximal or lower muscle weakness, calf pseudohypertrophy, hyperCKemia or cardiomyopathy, as in the cases of TCAP- or FKRP -related disorders and sarcoglycanopathies [1,2,4].…”

A novel noncoding FKRP mutation in early onset limb-girdle muscular dystrophy

“…Western blotting of pooled muscle biopsy cryosections followed the methods described previously. 7 Blotting with a core peptide antibody, AF6868, shows that our patient has reduced molecular weight alpha-dystroglycan that is very similar to a patient with homozygous c.826C>A FKRP mutations. Normal control muscle is designated as "C".…”

“…Thus, based on the clinical features, compound heterozygosity with a common FKRP mutation in 1 allele, reduced immunostaining for alpha-dystroglycan, abnormal glycosylation by western blot, Immunofluorescence evaluation of dystrophin, alpha-dystroglycan, and beta-dystroglycan were performed as described. 7 There is selectively reduced staining for alpha-dystroglycan using a matriglycan-specific antibody, IIH6 (C-H). The mosaic pattern of reduced to absent immunostaining is characteristic of milder dystroglycanopathy phenotypes (G).…”