Intrafamilial phenotypic variation in limb-girdle muscular dystrophy type 2C with compound heterozygous mutations

Takano, Atsushi; Bönnemann, Carsten G.; Honda, Hideo; Sakai, Masaharu; Feener, Chris A.; Kunkel, Louis M.; Sobue, Gen

doi:10.1002/(sici)1097-4598(200005)23:5<807::aid-mus20>3.0.co;2-0

Cited by 19 publications

(8 citation statements)

References 14 publications

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“…1O–R). This recapitulates results observed in LGMD‐2C γ‐sarcoglycan–deficient patients, where α‐, β‐, and δ‐sarcoglycan expression was sometimes detected at the plasma membrane 7, 16, 32, 35. This suggests that formation of the β‐, δ‐sarcoglycan core is required for progress through the biosynthetic pathway; furthermore, although α‐sarcoglycan–EGFP was exported out of the endoplasmic reticulum alone, it co‐localized with β‐ and δ‐sarcoglycan both at the plasma membrane and in endosomal compartments, but only when β‐ and δ‐sarcoglycan were expressed together.…”

Section: Resultssupporting

confidence: 88%

“…A deficiency of any single member of the sarcoglycan complex results in a concomitant loss of the other members of the complex 2, 4, 18. However, conflicting data have demonstrated that some residual α‐, β‐, and δ‐sarcoglycan protein may be present at the plasma membrane in LGMD‐2C (γ‐sarcoglycan–deficient) patients 3, 7, 14–16, 32, 35. This observation supports the concept that α‐, β‐, and δ‐sarcoglycan subunits are more tightly associated 33, 34…”

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confidence: 99%

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The β‐δ‐core of sarcoglycan is essential for deposition at the plasma membrane

2006

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Mutations of any of the sarcoglycan complex subunits (alpha, beta, delta, and gamma) cause limb-girdle muscular dystrophy. Furthermore, individual mutations lead to a reduction or loss of all other members of the complex. In some cases of limb-girdle muscular dystrophies, however, residual sarcoglycan expression has been documented. Therefore, in this study we tested the hypothesis that formation of specific sarcoglycan subcomplexes is crucial for plasma membrane deposition. Using co-immunoprecipitation assays, we demonstrated that beta- and delta-sarcoglycan interact with alpha-sarcoglycan and these two subunits must be co-expressed for export from the endoplasmic reticulum. Advanced light-microscopic imaging techniques demonstrated that co-expression of beta-sarcoglycan and delta-sarcoglycan is also responsible for delivery to and retention of sarcoglycan subcomplexes at the cell surface. These data suggest that formation of the beta-delta-core may promote the export and deposition of sarcoglycan subcomplexes at the plasma membrane, and therefore identifies a mechanism for sarcoglycan transport.

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Section: Resultssupporting

confidence: 88%

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confidence: 99%

The β‐δ‐core of sarcoglycan is essential for deposition at the plasma membrane

2006

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“…In comparison, our results indicate a much lower incidence (0.6%) of LGMD2C among patients suspected to have DMD. However, the low prevalence of LGMD2C in Japanese is in accordance with the few reports that have examined LCMD2C patients from Japan [18,19]. Regardless of these differences, the potential presence of LGMD2C needs to be considered when making a differential diagnosis of DMD, even in Japan.…”

Section: Discussionsupporting

confidence: 55%

“…We also identified the exon 6 deletion in three of four alleles in our two Japanese LGMD2C patients. This mutation has been previously reported to occur as a hemizygous condition in Japanese [19]. In Europe, this exon 6 deletion has been reported in both homozygous and hemizygous conditions [23].…”

Section: Discussionmentioning

confidence: 94%

“…Although originally reported to be a severe autosomal recessive muscular dystrophy that resembles DMD, LGMD2C has since been reported to have a heterogenous clinical course, even with identical mutations [19]. Initially, both of our LGMD2C patients were tentatively diagnosed as having DMD, even though both patients showed only very mild muscle weakness during the original observation period.…”

Section: Discussionmentioning

confidence: 95%

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Low incidence of limb-girdle muscular dystrophy type 2C revealed by a mutation study in Japanese patients clinically diagnosed with DMD

et al. 2010

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BackgroundLimb-girdle muscular dystrophy type 2C (LGMD2C) is an autosomal recessive muscle dystrophy that resembles Duchenne muscular dystrophy (DMD). Although DMD is known to affect one in every 3500 males regardless of race, a widespread founder mutation causing LGMD2C has been described in North Africa. However, the incidence of LGMD2C in Japanese has been unknown because the genetic background remains uncharacterized in many patients clinically diagnosed with DMD.MethodsWe enrolled 324 patients referred to the Kobe University Hospital with suspected DMD. Mutations in the dystrophin or the SGCG genes were analyzed using not only genomic DNA but also cDNA.ResultsIn 322 of the 324 patients, responsible mutations in the dystrophin were successfully revealed, confirming DMD diagnosis. The remaining two patients had normal dystrophin expression but absence of γ-sarcoglycan in skeletal muscle. Mutation analysis of the SGCG gene revealed homozygous deletion of exon 6 in one patient, while the other had a novel single nucleotide insertion in exon 7 in one allele and deletion of exon 6 in the other allele. These mutations created a stop codon that led to a γ-sarcoglycan deficiency, and we therefore diagnosed these two patients as having LGMD2C. Thus, the relative incidence of LGMD2C among Japanese DMD-like patients can be calculated as 1 in 161 patients suspected to have DMD (2 of 324 patients = 0.6%). Taking into consideration the DMD incidence for the overall population (1/3,500 males), the incidence of LGMD2C can be estimated as 1 per 560,000 or 1.8 per million.ConclusionsTo the best of our knowledge, this is the first study to demonstrate a low incidence of LGMD2C in the Japanese population.

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Sarcoglycanopathies and the risk of undetected deletion alleles in diagnosis

et al. 2005

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We have designed Multiplex Amplifiable Probe Hybridization (MAPH) probes for 28 exons of the sarcoglycan genes SGCA, SGCB, SGCG, and SGCD. The set was used to screen DNA from limb-girdle muscular dystrophy (LGMD) patients for the presence of pathogenic deletion or duplication mutations. An unexpected heterozygous deletion of SGCG exon 7 was detected in a patient from a consanguineous family in which a known c.525delT mutation segregates. The exon 7 deletion was inherited from the father, who was part of the consanguineous c.525delT branch of the family but who did not carry the c.525delT mutation. A similar, homozygous deletion had been identified in two unrelated LGMD patients from southern Italy. The deletion breakpoints were mapped, isolated, and sequenced, and were identical in all cases. Haplotype analysis showed the same alleles segregating with the mutation in all three patients, suggesting a common ancestor. Exonic deletions in sarcoglycanopathies appear to be rare events. However, we recommend screening for exonic deletions/duplications in patients where a mutation has not been identified in both alleles, as well as in seemingly homozygous cases where segregation of the mutations can not be confirmed in the parents.

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Intrafamilial phenotypic variation in limb-girdle muscular dystrophy type 2C with compound heterozygous mutations

Cited by 19 publications

References 14 publications

The β‐δ‐core of sarcoglycan is essential for deposition at the plasma membrane

The β‐δ‐core of sarcoglycan is essential for deposition at the plasma membrane

Low incidence of limb-girdle muscular dystrophy type 2C revealed by a mutation study in Japanese patients clinically diagnosed with DMD

Sarcoglycanopathies and the risk of undetected deletion alleles in diagnosis

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