ND20522
LCL from B-Lymphocyte
Description:
PRIMARY LATERAL SCLEROSIS
PARKINSONISM, OTHER
|
Repository
|
NINDS Repository
|
| Subcollection |
Parkinsonism |
|
Biopsy Source
|
Peripheral vein
|
|
Cell Type
|
B-Lymphocyte
|
|
Tissue Type
|
Blood
|
|
Transformant
|
Epstein-Barr Virus
|
|
Sample Source
|
LCL from B-Lymphocyte
|
|
Race
|
White
|
|
Subject Type
|
case-spouse
|
|
Family Type
|
NUCLEAR FAMILIES - ONE AFFECTED
|
|
Ethnicity
|
Hispanic/Latino
|
|
Country of Origin
|
USA
|
|
Family Member
|
1
|
|
Family History
|
N
|
|
Relation to Proband
|
proband
|
|
Species
|
Homo sapiens
|
|
Common Name
|
Human
|
| PDL at Senescence |
25 |
| |
| Gene |
SOD1 |
| Chromosomal Location |
21q22.11 |
| Allelic Variant 1 |
147450.0015; AMYOTROPHIC LATERAL SCLEROSIS, FAMILIAL, AUTOSOMAL RECESSIVE |
| Identified Mutation |
ASP91ALA; In 14 affected individuals from 4 unrelated Swedish or Finnish families with ALS (105400), Andersen et al. (1995) identified a homozygous mutation in exon 4 of the SOD1 gene, resulting in an asp90-to-ala (D90A) substitution. Erythrocyte SOD1 activity was essentially normal. The findings suggested that this mutation caused ALS by a gain of function rather than by loss, and that the D90A mutation was less detrimental than previously reported mutations. Consanguinity was present in several of the families. The age at onset of symptoms ranged from 37 to 94 years in 1 family in which all patients showed very similar disease phenotypes; symptoms began with cramps in the legs, which progressed to muscular atrophy and weakness. Upper motor neuron signs appeared after 1-4 years disease duration in all patients; none of the patients showed signs of intellectual impairment. In a second family, onset in 2 sibs was at the age of 40, with a phenotype similar to that of the first family. In a third family, 3 sibs had onset at ages 20, 36, and 22 years, respectively. Four patients with apparently sporadic ALS were also found to carry the mutations. Andersen et al. (1995) concluded that familial ALS due to mutation in the SOD1 gene exists in both autosomal dominant and autosomal recessive forms.
Robberecht et al. (1996) identified a heterozygous D90A mutation in affected members of 2 families with ALS and in a patient with apparently sporadic ALS. Aguirre et al. (1999) found the D90A mutation in heterozygous state in affected members of 2 families and in 1 apparently sporadic case of ALS. Direct sequencing of exons 1 through 5 showed no additional mutations in the SOD1 gene in these patients and the D90A mutation was not found on 150 normal chromosomes.
In a worldwide haplotype study of 28 pedigrees with the D90A mutation, Al-Chalabi et al. (1998) found that 20 recessive families shared the same founder haplotype, regardless of geographic location, whereas several founders existed for the 8 dominant families. The findings confirmed that D90A can act in a dominant fashion in keeping with all other SOD1 mutations. Al-Chalabi et al. (1998) proposed that a tightly linked protective factor modifies the toxic effect of mutant SOD1 in recessive families.
Gellera et al. (2001) found homozygosity for the D90A mutation in a sporadic case of ALS.
In 2 sibs with ALS from a family described by Khoris et al. (2000), Hand et al. (2001) identified compound heterozygosity for D90A and D96N (147450.0032). A third sib with the disease died before testing. Further examination of the family identified the D90A mutation alone in 2 unaffected members and the D96N mutation alone in 4 unaffected members. There were no individuals homozygous for either mutation, and no unaffected individual with both mutations was identified. Hand et al. (2001) concluded that both mutations, which occur in the same region of the protein, are required for disease. The authors emphasized that this is the first report of compound heterozygosity for the SOD1 gene in an ALS patient and suggested that the findings may have implications for the interpretation of inheritance patterns in ALS families.
Using PET scanning, Turner et al. (2007) found that ALS patients homozygous for the D90A substitution had a 12% decrease in 5-HT1A receptor (5HTRA1; 109760) binding potential compared to healthy controls. The decreased binding among patients was most significant in the temporal lobes. Patients with sporadic ALS without the D90A substitution had a 21% decrease in binding potential. Turner et al. (2007) suggested that patients with the D90A mutation may have decreased cortical vulnerability compared to other ALS patients, which may correlate with the slower progression observed in D90A carriers.
|
| PDL at Senescence |
25 |
| Split Ratio (Frequency) |
1:3 (3 Days) |
| 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 |
- |
|