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Phenotype-Genotype Analysis of Chinese Patients with Early-Onset LMNA-Related Muscular Dystrophy.

Tan D, Yang H, Yuan Y, Bonnemann C, Chang X, Wang S, Wu Y, Wu X, Xiong H - PLoS ONE (2015)

Bottom Line: Seven patients were diagnosed with Emery-Dreifuss muscular dystrophy (EDMD) and 14 were diagnosed with LMNA-associated congenital muscular dystrophy (L-CMD).Inflammatory change in biopsied muscle is a characteristic of early-stage L-CMD.Phenotype-genotype analysis determines that some mutations are well correlated with LMNA-related MD.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric, Peking University First Hospital, Beijing, China; Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, China.

ABSTRACT
This study aimed to analyze the correlation between the phenotype and genotype of Chinese patients with early-onset lamin A (LMNA)-related muscular dystrophy (MD). The clinical and myopathological data of 21 Chinese pediatric patients with early-onset LMNA-related MD were collected and analyzed. LMNA gene mutation analysis was performed by direct sequencing of genomic DNA. Sublocalization of wild-type and mutant proteins were observed by immunofluorescence using cultured fibroblasts and human embryonic kidney 293 (HEK 293) cell. Seven patients were diagnosed with Emery-Dreifuss muscular dystrophy (EDMD) and 14 were diagnosed with LMNA-associated congenital muscular dystrophy (L-CMD). Four biopsy specimens from the L-CMD cases exhibited inflammatory changes. Abnormal nuclear morphology was observed with both transmission electron microscopy and lamin A/C staining. We identified 10 novel and nine known LMNA gene mutations in the 21 patients. Some mutations (c.91G>A, c.94_96delAAG, c.116A>G, c.745C>T, c.746G>A, and c.1580G>C) were well correlated with EDMD or L-CMD. LMNA-related MD has a common symptom triad of muscle weakness, joint contractures, and cardiac involvement, but the severity of symptoms and disease progression differ greatly. Inflammatory change in biopsied muscle is a characteristic of early-stage L-CMD. Phenotype-genotype analysis determines that some mutations are well correlated with LMNA-related MD.

No MeSH data available.


Related in: MedlinePlus

Abnormal fibroblast nuclear morphology.Immunofluorescence staining of (A–C) control and (D–F) patient 7 was carried out using antibodies against (A, D) lamin A/C. (B, E) Corresponding Hoechst staining; (C, F) merged images.
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pone.0129699.g004: Abnormal fibroblast nuclear morphology.Immunofluorescence staining of (A–C) control and (D–F) patient 7 was carried out using antibodies against (A, D) lamin A/C. (B, E) Corresponding Hoechst staining; (C, F) merged images.

Mentions: Under immunofluorescence, dermal fibroblasts from patient 7, who carries the LMNAR48P/WT mutation, had abnormalities (35/100 diaminophenylindole [DAPI] nuclei) such as nuclei of unequal size and abnormal morphology as compared with control skin fibroblasts (4/100 DAPI nuclei) (Fig 4). We examined the effect of the four mutations (p.R48P, p.R249W, p.I373V, p.Ile497_Glu536del) on the subcellular localization of lamin A/C after transfection of mutant constructs into HEK 293 cells. Transfection of the wild-type construct resulted in normal lamin A/C localization at the inner nuclear membrane. However, lamin A/C immunoreactivity following transfection of the mutant constructs was abnormally distributed, forming distinct aggregates (Fig 5).


Phenotype-Genotype Analysis of Chinese Patients with Early-Onset LMNA-Related Muscular Dystrophy.

Tan D, Yang H, Yuan Y, Bonnemann C, Chang X, Wang S, Wu Y, Wu X, Xiong H - PLoS ONE (2015)

Abnormal fibroblast nuclear morphology.Immunofluorescence staining of (A–C) control and (D–F) patient 7 was carried out using antibodies against (A, D) lamin A/C. (B, E) Corresponding Hoechst staining; (C, F) merged images.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4476780&req=5

pone.0129699.g004: Abnormal fibroblast nuclear morphology.Immunofluorescence staining of (A–C) control and (D–F) patient 7 was carried out using antibodies against (A, D) lamin A/C. (B, E) Corresponding Hoechst staining; (C, F) merged images.
Mentions: Under immunofluorescence, dermal fibroblasts from patient 7, who carries the LMNAR48P/WT mutation, had abnormalities (35/100 diaminophenylindole [DAPI] nuclei) such as nuclei of unequal size and abnormal morphology as compared with control skin fibroblasts (4/100 DAPI nuclei) (Fig 4). We examined the effect of the four mutations (p.R48P, p.R249W, p.I373V, p.Ile497_Glu536del) on the subcellular localization of lamin A/C after transfection of mutant constructs into HEK 293 cells. Transfection of the wild-type construct resulted in normal lamin A/C localization at the inner nuclear membrane. However, lamin A/C immunoreactivity following transfection of the mutant constructs was abnormally distributed, forming distinct aggregates (Fig 5).

Bottom Line: Seven patients were diagnosed with Emery-Dreifuss muscular dystrophy (EDMD) and 14 were diagnosed with LMNA-associated congenital muscular dystrophy (L-CMD).Inflammatory change in biopsied muscle is a characteristic of early-stage L-CMD.Phenotype-genotype analysis determines that some mutations are well correlated with LMNA-related MD.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric, Peking University First Hospital, Beijing, China; Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, China.

ABSTRACT
This study aimed to analyze the correlation between the phenotype and genotype of Chinese patients with early-onset lamin A (LMNA)-related muscular dystrophy (MD). The clinical and myopathological data of 21 Chinese pediatric patients with early-onset LMNA-related MD were collected and analyzed. LMNA gene mutation analysis was performed by direct sequencing of genomic DNA. Sublocalization of wild-type and mutant proteins were observed by immunofluorescence using cultured fibroblasts and human embryonic kidney 293 (HEK 293) cell. Seven patients were diagnosed with Emery-Dreifuss muscular dystrophy (EDMD) and 14 were diagnosed with LMNA-associated congenital muscular dystrophy (L-CMD). Four biopsy specimens from the L-CMD cases exhibited inflammatory changes. Abnormal nuclear morphology was observed with both transmission electron microscopy and lamin A/C staining. We identified 10 novel and nine known LMNA gene mutations in the 21 patients. Some mutations (c.91G>A, c.94_96delAAG, c.116A>G, c.745C>T, c.746G>A, and c.1580G>C) were well correlated with EDMD or L-CMD. LMNA-related MD has a common symptom triad of muscle weakness, joint contractures, and cardiac involvement, but the severity of symptoms and disease progression differ greatly. Inflammatory change in biopsied muscle is a characteristic of early-stage L-CMD. Phenotype-genotype analysis determines that some mutations are well correlated with LMNA-related MD.

No MeSH data available.


Related in: MedlinePlus