GM26007
LCL from B-Lymphocyte
Description:
BETHLEM MYOPATHY
COLLAGEN, TYPE VI, ALPHA-1; COL6A1
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Repository
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NIGMS Human Genetic Cell Repository
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| Subcollection |
Heritable Diseases
CMD Specific
PIGI Consented Sample |
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Biopsy Source
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Peripheral vein
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Cell Type
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B-Lymphocyte
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Tissue Type
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Blood
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Transformant
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Epstein-Barr Virus
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Sample Source
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LCL from B-Lymphocyte
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Race
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White
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Ethnicity
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Not Hispanic/Latino
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Country of Origin
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USA
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Family History
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N
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Relation to Proband
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proband
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Confirmation
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Molecular characterization before cell line submission to CCR
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Species
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Homo sapiens
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Common Name
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Human
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Remarks
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| IDENTIFICATION OF SPECIES OF ORIGIN |
Species of Origin Confirmed by LINE assay |
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| Gene |
COL6A1 |
| Chromosomal Location |
21q22.3 |
| Allelic Variant 1 |
120220.0002; BETHLEM MYOPATHY |
| Identified Mutation |
IVS11AS, G-A, -1; In a patient with Bethlem myopathy, Lamande et al. (1998) found an approximately 50% reduction in the level of COL6A1 mRNA relative to COL6A2 and COL6A3 mRNAs. Since nonsense-mediated mRNA decay results in decreased steady-state mRNA levels and is a common but often overlooked consequence of mutations that introduce an in-frame premature stop codon, they sought a COL6A1 translocation termination mutation using the protein truncation test (Roest et al., 1993). Because protein synthesis inhibitors had been shown to reverse the decay of mRNAs containing premature stop codons, they treated the Bethlem myopathy fibroblasts with cycloheximide before RNA extraction in an attempt to stabilize any mRNAs that might have contained a mutation of this class. With these steps they detected, in the patient with Bethlem myopathy, deletion of a G residue from a group of 3 that are interrupted in the COL6A1 gene by intron 11. To determine the precise nature of the gene mutation, genomic DNA from 10 normal and 9 affected family members was PCR amplified using primers within exons 10 and 13, and directly sequenced. The analysis demonstrated that the mutation was a heterozygous G-to-A transition at the -1 position of the consensus acceptor splice site of intron 11. The effect of the mutation was not to remove the splice site but to move it 3-prime by 1 base, resulting in the deletion of a G from the mRNA.
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| Demographic Data |
| Relation to Proband |
proband |
| Age at Sampling |
37 YR |
| Sex |
Female |
| Age of Onset(If not a control) |
5 YR |
| Hispanic or Latino/Not Hispanic or Latino |
Not Hispanic/Latino |
| Racial Category |
White |
| Country |
USA |
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| Data Elements |
| Clinical Element Type: General NIGMS Catalog Remarks |
| (Baseline) |
| Mutation Information |
| Gene, variant, consequence, and exon number: |
COL6A1, C.931-1G>A, SPLICING, INTRON 11 |
| Zygosity: |
Heterozygous |
| Other variants: |
ONE COPY OF EACH OF THREE VARIANTS OF UNKNOWN CLINICAL SIGNIFICANCE WERE DETECTED IN THIS INDIVIDUAL:
GAA, C.1828G>A, P.A610T, EXON 13
SYNE1, C.9955G>A, P.D3319N, EXON 62
TTN, C.11014A>G, P.K3672E, EXON 47 |
| Age of Symptom Onset and Age at Diagnosis |
| Age of Symptom Onset: |
5 YEARS |
| In Utero History Information |
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| Birth History Information |
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| Dysmorphic Features |
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| Neurological Symptoms |
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| Optical and Audiological Symptoms |
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| Musculoskeletal Symptoms |
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| Developmental Milestones |
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| Holding Head Up Without Assistance: |
Achieved and maintained |
| Sitting Without Assistance: |
Achieved and maintained |
| Walking Without Assistance: |
Achieved and maintained |
| Running: |
Achieved and maintained |
| Gastrointestinal Symptoms |
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| Genitourinary Symptoms |
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| Respiratory and Cardiovascular Symptoms |
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| Cognitive and Behavioral Symptoms |
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| Additional Information |
| Testing Performed |
| Musculoskeletal and Developmental Testing: |
CREATINE KINASE: 698 MCG/L |
| Treatments and Assistive Devices |
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| Medications |
| Family History |
| Remarks |
Clinically affected. Muscle biopsy at age of 7 showed increased fiber size variability, some fiber splitting, occasional regular fibers without inflammatory increased connective tissue. Muscle biopsy at age of 11 showed polygonal fibers with dystrophic central nuclei and degeneration/regeneration, with striking type I predominance. Creatine kinase level test at 698 mcg/l at age of 23. Muscle biopsy at age of 30 showed wide variation in fiber size due to atrophic and hypertrophic fibers. There was severe endomysial fibrosis and fatty infiltration. Heterozygous mild pathogenic mutation C.931-1G>A in the COL6A1 gene. |
| Split Ratio |
1:3 |
| Temperature |
37 C |
| Percent CO2 |
5% |
| Percent O2 |
AMBIENT |
| Medium |
Roswell Park Memorial Institute Medium 1640 with 2mM L-glutamine or equivalent |
| Serum |
15% fetal bovine serum Not Inactivated |
| Substrate |
None specified |
| Subcultivation Method |
dilution - add fresh medium |
| Supplement |
- |
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