Two families with familial amyotrophic lateral sclerosis are linked to a novel locus on chromosome 16q

Deborah M. Ruddy; Matthew J. Parton; Ammar Al-Chalabi; Cathryn M. Lewis; Caroline Vance; Bradley N. Smith; P. Nigel Leigh; John F. Powell; Teepu Siddique; Eelco Postumus Meyjes; Frank Baas; Vianney De Jong; Christopher E. Shaw

doi:10.1086/377157

Two families with familial amyotrophic lateral sclerosis are linked to a novel locus on chromosome 16q

Deborah M. Ruddy, Matthew J. Parton, Ammar Al-Chalabi, Cathryn M. Lewis, Caroline Vance, Bradley N. Smith, P. Nigel Leigh, John F. Powell, Teepu Siddique, Eelco Postumus Meyjes, Frank Baas, Vianney De Jong, Christopher E. Shaw^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

76 Scopus citations

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset disease in which motor neurons in the brain and spinal cord degenerate by largely unknown mechanisms. ALS is familial (FALS) in 10% of cases, and the inheritance is usually dominant, with variable penetrance. Mutations in copper/zinc super oxide dismutase (SOD1) are found in 20% of familial and 3% of sporadic ALS cases. Five families with ALS and frontotemporal dementia (ALS-FTD) are linked to 9q21, whereas one family with pure ALS is linked to 18q21. We identified two large European families with ALS without SOD1 mutations or linkage to known FALS loci and conducted a genomewide linkage screen using 400 microsatellite markers. In both families, two-point LOD scores >1 and a haplotype segregating with disease were demonstrated only across regions of chromosome 16. Subsequent fine mapping in family 1 gave a maximum two-point LOD score of 3.62 at D1683137 and a three-point LOD score of 3.85 for markers D168415 and D1683137. Haplotype analysis revealed no recombination >∼30 cM, (flanking markers at D1683075 and D1683112). The maximum two-point LOD score for family 2 was 1.84 at D168415, and the three-point LOD score was 2.10 for markers D168419 and D168415. Definite recombination occurred in several individuals, which narrowed the shared haplotype in affected individuals to a 10.1-cM region (flanking markers: D1683396 and D1683112). The region shared by both families on chromosome 16q12 corresponds to ∼4.5 Mb on the Marshfield map. Bioinformatic analysis of the region has identified 18 known genes and 70 predicted genes in this region, and sequencing of candidate genes has now begun.

Original language	English (US)
Pages (from-to)	390-396
Number of pages	7
Journal	American journal of human genetics
Volume	73
Issue number	2
DOIs	https://doi.org/10.1086/377157
State	Published - Aug 1 2003
Externally published	Yes

Funding

First and foremost, the authors thank the families who contributed to this project. This work was supported by clinical training fellowships from the Medical Research Council U.K. (to D.R.) and Wellcome Trust (to M.J.P.), Joint Research Committee of King’s College Hospital London (to B.N.S), Psychiatry Research Trust of the Institute of Psychiatry (to B.N.S. and C.V.), and the Motor Neurone Disease Association U.K.

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1086/377157

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Ruddy, D. M., Parton, M. J., Al-Chalabi, A., Lewis, C. M., Vance, C., Smith, B. N., Leigh, P. N., Powell, J. F., Siddique, T., Meyjes, E. P., Baas, F., De Jong, V., & Shaw, C. E. (2003). Two families with familial amyotrophic lateral sclerosis are linked to a novel locus on chromosome 16q. American journal of human genetics, 73(2), 390-396. https://doi.org/10.1086/377157

@article{d00fdc11932b4e56a2cb67a4c590fa87,

title = "Two families with familial amyotrophic lateral sclerosis are linked to a novel locus on chromosome 16q",

abstract = "Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset disease in which motor neurons in the brain and spinal cord degenerate by largely unknown mechanisms. ALS is familial (FALS) in 10% of cases, and the inheritance is usually dominant, with variable penetrance. Mutations in copper/zinc super oxide dismutase (SOD1) are found in 20% of familial and 3% of sporadic ALS cases. Five families with ALS and frontotemporal dementia (ALS-FTD) are linked to 9q21, whereas one family with pure ALS is linked to 18q21. We identified two large European families with ALS without SOD1 mutations or linkage to known FALS loci and conducted a genomewide linkage screen using 400 microsatellite markers. In both families, two-point LOD scores >1 and a haplotype segregating with disease were demonstrated only across regions of chromosome 16. Subsequent fine mapping in family 1 gave a maximum two-point LOD score of 3.62 at D1683137 and a three-point LOD score of 3.85 for markers D168415 and D1683137. Haplotype analysis revealed no recombination >∼30 cM, (flanking markers at D1683075 and D1683112). The maximum two-point LOD score for family 2 was 1.84 at D168415, and the three-point LOD score was 2.10 for markers D168419 and D168415. Definite recombination occurred in several individuals, which narrowed the shared haplotype in affected individuals to a 10.1-cM region (flanking markers: D1683396 and D1683112). The region shared by both families on chromosome 16q12 corresponds to ∼4.5 Mb on the Marshfield map. Bioinformatic analysis of the region has identified 18 known genes and 70 predicted genes in this region, and sequencing of candidate genes has now begun.",

author = "Ruddy, {Deborah M.} and Parton, {Matthew J.} and Ammar Al-Chalabi and Lewis, {Cathryn M.} and Caroline Vance and Smith, {Bradley N.} and Leigh, {P. Nigel} and Powell, {John F.} and Teepu Siddique and Meyjes, {Eelco Postumus} and Frank Baas and {De Jong}, Vianney and Shaw, {Christopher E.}",

note = "Funding Information: First and foremost, the authors thank the families who contributed to this project. This work was supported by clinical training fellowships from the Medical Research Council U.K. (to D.R.) and Wellcome Trust (to M.J.P.), Joint Research Committee of King{\textquoteright}s College Hospital London (to B.N.S), Psychiatry Research Trust of the Institute of Psychiatry (to B.N.S. and C.V.), and the Motor Neurone Disease Association U.K. ",

year = "2003",

month = aug,

day = "1",

doi = "10.1086/377157",

language = "English (US)",

volume = "73",

pages = "390--396",

journal = "American journal of human genetics",

issn = "0002-9297",

publisher = "Cell Press",

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T1 - Two families with familial amyotrophic lateral sclerosis are linked to a novel locus on chromosome 16q

AU - Ruddy, Deborah M.

AU - Parton, Matthew J.

AU - Al-Chalabi, Ammar

AU - Lewis, Cathryn M.

AU - Vance, Caroline

AU - Smith, Bradley N.

AU - Leigh, P. Nigel

AU - Powell, John F.

AU - Siddique, Teepu

AU - Meyjes, Eelco Postumus

AU - Baas, Frank

AU - De Jong, Vianney

AU - Shaw, Christopher E.

N1 - Funding Information: First and foremost, the authors thank the families who contributed to this project. This work was supported by clinical training fellowships from the Medical Research Council U.K. (to D.R.) and Wellcome Trust (to M.J.P.), Joint Research Committee of King’s College Hospital London (to B.N.S), Psychiatry Research Trust of the Institute of Psychiatry (to B.N.S. and C.V.), and the Motor Neurone Disease Association U.K.

PY - 2003/8/1

Y1 - 2003/8/1

N2 - Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset disease in which motor neurons in the brain and spinal cord degenerate by largely unknown mechanisms. ALS is familial (FALS) in 10% of cases, and the inheritance is usually dominant, with variable penetrance. Mutations in copper/zinc super oxide dismutase (SOD1) are found in 20% of familial and 3% of sporadic ALS cases. Five families with ALS and frontotemporal dementia (ALS-FTD) are linked to 9q21, whereas one family with pure ALS is linked to 18q21. We identified two large European families with ALS without SOD1 mutations or linkage to known FALS loci and conducted a genomewide linkage screen using 400 microsatellite markers. In both families, two-point LOD scores >1 and a haplotype segregating with disease were demonstrated only across regions of chromosome 16. Subsequent fine mapping in family 1 gave a maximum two-point LOD score of 3.62 at D1683137 and a three-point LOD score of 3.85 for markers D168415 and D1683137. Haplotype analysis revealed no recombination >∼30 cM, (flanking markers at D1683075 and D1683112). The maximum two-point LOD score for family 2 was 1.84 at D168415, and the three-point LOD score was 2.10 for markers D168419 and D168415. Definite recombination occurred in several individuals, which narrowed the shared haplotype in affected individuals to a 10.1-cM region (flanking markers: D1683396 and D1683112). The region shared by both families on chromosome 16q12 corresponds to ∼4.5 Mb on the Marshfield map. Bioinformatic analysis of the region has identified 18 known genes and 70 predicted genes in this region, and sequencing of candidate genes has now begun.

AB - Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset disease in which motor neurons in the brain and spinal cord degenerate by largely unknown mechanisms. ALS is familial (FALS) in 10% of cases, and the inheritance is usually dominant, with variable penetrance. Mutations in copper/zinc super oxide dismutase (SOD1) are found in 20% of familial and 3% of sporadic ALS cases. Five families with ALS and frontotemporal dementia (ALS-FTD) are linked to 9q21, whereas one family with pure ALS is linked to 18q21. We identified two large European families with ALS without SOD1 mutations or linkage to known FALS loci and conducted a genomewide linkage screen using 400 microsatellite markers. In both families, two-point LOD scores >1 and a haplotype segregating with disease were demonstrated only across regions of chromosome 16. Subsequent fine mapping in family 1 gave a maximum two-point LOD score of 3.62 at D1683137 and a three-point LOD score of 3.85 for markers D168415 and D1683137. Haplotype analysis revealed no recombination >∼30 cM, (flanking markers at D1683075 and D1683112). The maximum two-point LOD score for family 2 was 1.84 at D168415, and the three-point LOD score was 2.10 for markers D168419 and D168415. Definite recombination occurred in several individuals, which narrowed the shared haplotype in affected individuals to a 10.1-cM region (flanking markers: D1683396 and D1683112). The region shared by both families on chromosome 16q12 corresponds to ∼4.5 Mb on the Marshfield map. Bioinformatic analysis of the region has identified 18 known genes and 70 predicted genes in this region, and sequencing of candidate genes has now begun.

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JO - American journal of human genetics

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Two families with familial amyotrophic lateral sclerosis are linked to a novel locus on chromosome 16q

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