ND09576

Overview

Repository

NINDS Repository

Subcollection

Motor Neuron Disease

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

Not Hispanic/Latino

Country of Origin

USA

Family Member

Family History

Relation to Proband

proband

Species

Homo sapiens

Common Name

Human

Characterizations

Gene

C9ORF72

Chromosomal Location

9p21

Allelic Variant 1

614260.0001; FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS

Identified Mutation

(GGGGCC)n EXPANSION; DeJesus-Hernandez et al. (2011) identified a polymorphic hexanucleotide repeat (GGGGCC) located between the noncoding exons 1a and 1b of the C9ORF72 gene. The maximum size of the repeat in healthy controls was 23 units, whereas it was expanded in members of a large family with frontotemporal dementia and/or anyotrophic lateral sclerosis mapping to chromosome 9p21 (FTDALS; 105550) (Boxer et al., 2011). Affected individuals had expanded repeat units ranging from 700 to 1,600. Further analysis identified this expanded hexanucleotide repeat in 16 (61.5%) of a series of 26 families with the disorder, as well as in 11.7% of familial FTD and 23.5% of familial ALS from 3 patient series. Sporadic cases with the expansion were also identified. Overall, 75 (10.4%) of 722 unrelated patients with FTD, ALS, or both were found to carry an expanded GGGGCC repeat, and DeJesus-Hernandez et al. (2011) concluded that it is the most common genetic abnormality in FTD/ALS. Longer repeats were associated with the A allele at SNP rs3849942, which marked a disease haplotype. The expanded repeat is located in the promoter region of C9ORF72 transcript variant 1 and in intron 1 of transcript variants 2 and 3. Tissue from affected individuals showed reduced or absent mRNA levels of C9ORF72 variants 1 and 3 compared to nonrepeat carriers, consistent with a loss-of-function mechanism. However, protein levels of these variants were similar to controls, and analysis of patient frontal cortex and spinal cord tissue showed that the transcribed expanded GGGGCC repeat formed nuclear RNA foci, suggesting a gain-of-function mechanism. Simultaneously and independently, Renton et al. (2011) identified the GGGGCC expanded repeat as a cause of FTD/ALS in families reported by Pearson et al. (2011) and Mok et al. (2011). The expanded repeat was also found in 46.4% of Finnish familial ALS cases and in 21% of sporadic cases. PCR assays showed that Finnish controls had between 0 and 22 repeats. FISH studies showed that the expansion in a family from Wales (Pearson et al., 2011) was at least 250 repeats. In addition, an expanded repeat was found in 102 (38.1%) of 268 familial ALS probands of European origin. Real-time RT-PCR analysis of expression in frontal cortex tissue from patients and controls did not detect conclusive changes in RNA levels and produced inconsistent results. Nevertheless, Renton et al. (2011) postulated that a disruption in RNA metabolism likely underlies this disorder.

Publications

Abramzon Y, Johnson JO, Scholz SW, Taylor JP, Brunetti M, Calvo A, Mandrioli J, Benatar M, Mora G, Restagno G, Chiò A, Traynor BJ, Valosin-containing protein (VCP) mutations in sporadic amyotrophic lateral sclerosis Neurobiology of aging33:2231.e1-6 2012

PubMed ID: 22572540

Dunckley T, Huentelman MJ, Craig DW, Pearson JV, Szelinger S, Joshipura K, Halperin RF, Stamper C, Jensen KR, Letizia D, Hesterlee SE, Pestronk A, Levine T, Bertorini T, Graves MC, Mozaffar T, Jackson CE, Bosch P, McVey A, Dick A, Barohn R, Lomen-Hoerth C, Rosenfeld J, O'connor DT, Zhang K, Crook R, Ryberg H, Hutton M, Katz J, Simpson EP, Mitsumoto H, Bowser R, Miller RG, Appel SH, Stephan DA, Whole-Genome Analysis of Sporadic Amyotrophic Lateral Sclerosis Neurobiology of aging33:2231.e1-6 2007

PubMed ID: 17671248

Rademakers R, Baker M, Gass J, Adamson J, Huey ED, Momeni P, Spina S, Coppola G, Karydas AM, Stewart H, Johnson N, Hsiung GY, Kelley B, Kuntz K, Steinbart E, Wood EM, Yu CE, Josephs K, Sorenson E, Womack KB, Weintraub S, Pickering-Brown SM, Schofield PR, Brooks WS, Van Deerlin VM, Snowden J, Clark CM, Kertesz A, Boylan K, Ghetti B, Neary D, Schellenberg GD, Beach TG, Mesulam M, Mann D, Grafman J, Mackenzie IR, Feldman H, Bird T, Petersen R, Knopman D, Boeve B, Geschwind DH, Miller B, Wszolek Z, Lippa C, Bigio EH, Dickson D, Graff-Radford N, Hutton M, Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C-->T (Arg493X) mutation: an international initiative Lancet neurology6:857-68 2007

PubMed ID: 17826340

Schymick JC, Scholz SW, Fung HC, Britton A, Arepalli S, Gibbs JR, Lombardo F, Matarin M, Kasperaviciute D, Hernandez DG, Crews C, Bruijn L, Rothstein J, Mora G, Restagno G, Chiò A, Singleton A, Hardy J, Traynor BJ, Genome-wide genotyping in amyotrophic lateral sclerosis and neurologically normal controls: first stage analysis and public release of data Lancet neurology6:322-8 2007

PubMed ID: 17362836

External Links

NCBI GTR

105400 AMYOTROPHIC LATERAL SCLEROSIS 1; ALS1

OMIM

105400 AMYOTROPHIC LATERAL SCLEROSIS 1; ALS1

Omim Description

ALS

AMYOTROPHIC LATERAL SCLEROSIS

AMYOTROPHIC LATERAL SCLEROSIS, TYPE 1; ALS1

dbGaP Link

phs000101.v5.p1

Images

View

pedigree

Culture Protocols

Split Ratio (Frequency)

1:5 (4 Days)

Temperature

37 C

Percent CO2

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

Description:

AMYOTROPHIC LATERAL SCLEROSIS 1; ALS1
ALS PANEL CAUCASIAN FROM THE US
ALS PANEL; UPPER-LIMB ONSET; DEFINITE AND PROBABLE
ALS PANEL; UPPER-LIMB ONSET; DEFINITE AND PROBABLE ALS

Affected:

Yes

Gender:

Female

Age:

58 YR (At Sampling)

Overview

Characterizations

Phenotypic Data

Publications

External Links

Images

Culture Protocols

Description:

AMYOTROPHIC LATERAL SCLEROSIS 1; ALS1 ALS PANEL CAUCASIAN FROM THE US ALS PANEL; UPPER-LIMB ONSET; DEFINITE AND PROBABLE ALS PANEL; UPPER-LIMB ONSET; DEFINITE AND PROBABLE ALS

Affected:

Yes

Gender:

Female

Age:

58 YR (At Sampling)

Overview

Characterizations

Phenotypic Data

Publications

External Links

Images

Culture Protocols

AMYOTROPHIC LATERAL SCLEROSIS 1; ALS1
ALS PANEL CAUCASIAN FROM THE US
ALS PANEL; UPPER-LIMB ONSET; DEFINITE AND PROBABLE
ALS PANEL; UPPER-LIMB ONSET; DEFINITE AND PROBABLE ALS