An unstable trinucleotide-repeat region on chromosome 13 implicated in spinocerebellar ataxia: A common expansion locus

John B. Vincent; Maria L. Neves-Pereira; Andrew D. Paterson; Etsuko Yamamoto; Sagar V. Parikh; Fabio Macciardi; Hugh M D Gurling; Steve G. Potkin; Carlos N. Pato; Antonio Macedo; Maria Kovacs; Marilyn Davies; Jeffrey A. Lieberman; Herbert Y. Meltzer; Arturas Petronis; James L. Kennedy

doi:10.1086/302803

An unstable trinucleotide-repeat region on chromosome 13 implicated in spinocerebellar ataxia: A common expansion locus

John B. Vincent^*, Maria L. Neves-Pereira, Andrew D. Paterson, Etsuko Yamamoto, Sagar V. Parikh, Fabio Macciardi, Hugh M D Gurling, Steve G. Potkin, Carlos N. Pato, Antonio Macedo, Maria Kovacs, Marilyn Davies, Jeffrey A. Lieberman, Herbert Y. Meltzer, Arturas Petronis, James L. Kennedy

^*Corresponding author for this work

Psychiatry and Behavioral Sciences

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

77 Scopus citations

Abstract

Larger CAG/CTG trinucleotide-repeat tracts in individuals affected with schizophrenia (SCZ) and bipolar affective disorder (BPAD) in comparison with control individuals have previously been reported, implying a possible etiological role for trinucleotide repeats in these diseases. Two unstable CAG/CTG repeats, SEF2-1B and ERDA1, have recently been cloned, and studies indicate that the majority of individuals with large repeats as detected by repeat-expansion detection (RED) have large repeat alleles at these loci. These repeats do not show association of large alleles with either BPAD or SCZ. Using RED, we have identified a BPAD individual with a very large CAG/CTG repeat that is not due to expansion at SEF2-1B or ERDA1. From this individual's DNA, we have cloned a highly polymorphic trinucleotide repeat consisting of (CTA)(n) (CTG)(n), which is very long (~1,800 bp) in this patient. The repeat region localizes to chromosome 13q21, within 1.2 cM of fragile site FRA13C. Repeat alleles in our sample were unstable in 13 (5.6%) of 231 meioses. Large alleles (>100 repeats) were observed in 14 (1.25%) of 1,120 patients with psychosis, borderline personality disorder, or juvenile- onset depression and in 5 (.7%) of 710 healthy controls. Very large alleles were also detected for Centre d'Etude Polymorphisme Humaine (CEPH) reference family 1334. This triplet expansion has recently been reported to be the cause of spinocerebellar ataxia type 8 (SCA8); however, none of our large alleles above the disease threshold occurred in individuals either affected by SCA or with known family history of SCA. The high frequency of large alleles at this locus is inconsistent with the much rarer occurrence of SCA8. Thus, it seems unlikely that expansion alone causes SCA8; other genetic mechanisms may be necessary to explain SCA8 etiology.

Original language	English (US)
Pages (from-to)	819-829
Number of pages	11
Journal	American journal of human genetics
Volume	66
Issue number	3
DOIs	https://doi.org/10.1086/302803
State	Published - 2000

Funding

Much gratitude is owed to Jennifer Skaug, Seema Khan, Barbara Kallam, and Jo-Anne Herbrick, at the Centre for Applied Genomics, and the Hospital for Sick Children, for help with the sequencing and mapping work. We also thank Dr. Vural Ozdemir for providing patient DNA samples. The efforts of Tasha Cate at Centre for Addiction and Mental Health in compiling much of the demographic data are much appreciated. This work was supported by funding from the Scottish Rite Schizophrenia Research Program, the Ontario Mental Health Foundation (OMHF), the Medical Research Council of Canada (MRC; grant MT15007), and the National Alliance for Research on Schizophrenia and Depression. Partial support was also obtained from National Institute for Mental Health grants MH33990 and POIMH56193. The BPAD trio collection was funded by Axys Pharmaceuticals. J.B.V. is a Medical Research Council/ Schizophrenia Society of Canada Research Fellow; A.D.P. is an MRC Research Fellow, and A.P. holds an OMHF New Investigator Fellowship.

ASJC Scopus subject areas

Genetics
Genetics(clinical)

Access to Document

10.1086/302803

Cite this

Vincent, J. B., Neves-Pereira, M. L., Paterson, A. D., Yamamoto, E., Parikh, S. V., Macciardi, F., Gurling, H. M. D., Potkin, S. G., Pato, C. N., Macedo, A., Kovacs, M., Davies, M., Lieberman, J. A., Meltzer, H. Y., Petronis, A., & Kennedy, J. L. (2000). An unstable trinucleotide-repeat region on chromosome 13 implicated in spinocerebellar ataxia: A common expansion locus. American journal of human genetics, 66(3), 819-829. https://doi.org/10.1086/302803

@article{f7e1be731b3347cdb0c6d01de96f2817,

title = "An unstable trinucleotide-repeat region on chromosome 13 implicated in spinocerebellar ataxia: A common expansion locus",

abstract = "Larger CAG/CTG trinucleotide-repeat tracts in individuals affected with schizophrenia (SCZ) and bipolar affective disorder (BPAD) in comparison with control individuals have previously been reported, implying a possible etiological role for trinucleotide repeats in these diseases. Two unstable CAG/CTG repeats, SEF2-1B and ERDA1, have recently been cloned, and studies indicate that the majority of individuals with large repeats as detected by repeat-expansion detection (RED) have large repeat alleles at these loci. These repeats do not show association of large alleles with either BPAD or SCZ. Using RED, we have identified a BPAD individual with a very large CAG/CTG repeat that is not due to expansion at SEF2-1B or ERDA1. From this individual's DNA, we have cloned a highly polymorphic trinucleotide repeat consisting of (CTA)(n) (CTG)(n), which is very long (~1,800 bp) in this patient. The repeat region localizes to chromosome 13q21, within 1.2 cM of fragile site FRA13C. Repeat alleles in our sample were unstable in 13 (5.6%) of 231 meioses. Large alleles (>100 repeats) were observed in 14 (1.25%) of 1,120 patients with psychosis, borderline personality disorder, or juvenile- onset depression and in 5 (.7%) of 710 healthy controls. Very large alleles were also detected for Centre d'Etude Polymorphisme Humaine (CEPH) reference family 1334. This triplet expansion has recently been reported to be the cause of spinocerebellar ataxia type 8 (SCA8); however, none of our large alleles above the disease threshold occurred in individuals either affected by SCA or with known family history of SCA. The high frequency of large alleles at this locus is inconsistent with the much rarer occurrence of SCA8. Thus, it seems unlikely that expansion alone causes SCA8; other genetic mechanisms may be necessary to explain SCA8 etiology.",

author = "Vincent, {John B.} and Neves-Pereira, {Maria L.} and Paterson, {Andrew D.} and Etsuko Yamamoto and Parikh, {Sagar V.} and Fabio Macciardi and Gurling, {Hugh M D} and Potkin, {Steve G.} and Pato, {Carlos N.} and Antonio Macedo and Maria Kovacs and Marilyn Davies and Lieberman, {Jeffrey A.} and Meltzer, {Herbert Y.} and Arturas Petronis and Kennedy, {James L.}",

note = "Funding Information: Much gratitude is owed to Jennifer Skaug, Seema Khan, Barbara Kallam, and Jo-Anne Herbrick, at the Centre for Applied Genomics, and the Hospital for Sick Children, for help with the sequencing and mapping work. We also thank Dr. Vural Ozdemir for providing patient DNA samples. The efforts of Tasha Cate at Centre for Addiction and Mental Health in compiling much of the demographic data are much appreciated. This work was supported by funding from the Scottish Rite Schizophrenia Research Program, the Ontario Mental Health Foundation (OMHF), the Medical Research Council of Canada (MRC; grant MT15007), and the National Alliance for Research on Schizophrenia and Depression. Partial support was also obtained from National Institute for Mental Health grants MH33990 and POIMH56193. The BPAD trio collection was funded by Axys Pharmaceuticals. J.B.V. is a Medical Research Council/ Schizophrenia Society of Canada Research Fellow; A.D.P. is an MRC Research Fellow, and A.P. holds an OMHF New Investigator Fellowship. ",

year = "2000",

doi = "10.1086/302803",

language = "English (US)",

volume = "66",

pages = "819--829",

journal = "American journal of human genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "3",

}

Vincent, JB, Neves-Pereira, ML, Paterson, AD, Yamamoto, E, Parikh, SV, Macciardi, F, Gurling, HMD, Potkin, SG, Pato, CN, Macedo, A, Kovacs, M, Davies, M, Lieberman, JA, Meltzer, HY, Petronis, A & Kennedy, JL 2000, 'An unstable trinucleotide-repeat region on chromosome 13 implicated in spinocerebellar ataxia: A common expansion locus', American journal of human genetics, vol. 66, no. 3, pp. 819-829. https://doi.org/10.1086/302803

TY - JOUR

T1 - An unstable trinucleotide-repeat region on chromosome 13 implicated in spinocerebellar ataxia

T2 - A common expansion locus

AU - Vincent, John B.

AU - Neves-Pereira, Maria L.

AU - Paterson, Andrew D.

AU - Yamamoto, Etsuko

AU - Parikh, Sagar V.

AU - Macciardi, Fabio

AU - Gurling, Hugh M D

AU - Potkin, Steve G.

AU - Pato, Carlos N.

AU - Macedo, Antonio

AU - Kovacs, Maria

AU - Davies, Marilyn

AU - Lieberman, Jeffrey A.

AU - Meltzer, Herbert Y.

AU - Petronis, Arturas

AU - Kennedy, James L.

N1 - Funding Information: Much gratitude is owed to Jennifer Skaug, Seema Khan, Barbara Kallam, and Jo-Anne Herbrick, at the Centre for Applied Genomics, and the Hospital for Sick Children, for help with the sequencing and mapping work. We also thank Dr. Vural Ozdemir for providing patient DNA samples. The efforts of Tasha Cate at Centre for Addiction and Mental Health in compiling much of the demographic data are much appreciated. This work was supported by funding from the Scottish Rite Schizophrenia Research Program, the Ontario Mental Health Foundation (OMHF), the Medical Research Council of Canada (MRC; grant MT15007), and the National Alliance for Research on Schizophrenia and Depression. Partial support was also obtained from National Institute for Mental Health grants MH33990 and POIMH56193. The BPAD trio collection was funded by Axys Pharmaceuticals. J.B.V. is a Medical Research Council/ Schizophrenia Society of Canada Research Fellow; A.D.P. is an MRC Research Fellow, and A.P. holds an OMHF New Investigator Fellowship.

PY - 2000

Y1 - 2000

N2 - Larger CAG/CTG trinucleotide-repeat tracts in individuals affected with schizophrenia (SCZ) and bipolar affective disorder (BPAD) in comparison with control individuals have previously been reported, implying a possible etiological role for trinucleotide repeats in these diseases. Two unstable CAG/CTG repeats, SEF2-1B and ERDA1, have recently been cloned, and studies indicate that the majority of individuals with large repeats as detected by repeat-expansion detection (RED) have large repeat alleles at these loci. These repeats do not show association of large alleles with either BPAD or SCZ. Using RED, we have identified a BPAD individual with a very large CAG/CTG repeat that is not due to expansion at SEF2-1B or ERDA1. From this individual's DNA, we have cloned a highly polymorphic trinucleotide repeat consisting of (CTA)(n) (CTG)(n), which is very long (~1,800 bp) in this patient. The repeat region localizes to chromosome 13q21, within 1.2 cM of fragile site FRA13C. Repeat alleles in our sample were unstable in 13 (5.6%) of 231 meioses. Large alleles (>100 repeats) were observed in 14 (1.25%) of 1,120 patients with psychosis, borderline personality disorder, or juvenile- onset depression and in 5 (.7%) of 710 healthy controls. Very large alleles were also detected for Centre d'Etude Polymorphisme Humaine (CEPH) reference family 1334. This triplet expansion has recently been reported to be the cause of spinocerebellar ataxia type 8 (SCA8); however, none of our large alleles above the disease threshold occurred in individuals either affected by SCA or with known family history of SCA. The high frequency of large alleles at this locus is inconsistent with the much rarer occurrence of SCA8. Thus, it seems unlikely that expansion alone causes SCA8; other genetic mechanisms may be necessary to explain SCA8 etiology.

AB - Larger CAG/CTG trinucleotide-repeat tracts in individuals affected with schizophrenia (SCZ) and bipolar affective disorder (BPAD) in comparison with control individuals have previously been reported, implying a possible etiological role for trinucleotide repeats in these diseases. Two unstable CAG/CTG repeats, SEF2-1B and ERDA1, have recently been cloned, and studies indicate that the majority of individuals with large repeats as detected by repeat-expansion detection (RED) have large repeat alleles at these loci. These repeats do not show association of large alleles with either BPAD or SCZ. Using RED, we have identified a BPAD individual with a very large CAG/CTG repeat that is not due to expansion at SEF2-1B or ERDA1. From this individual's DNA, we have cloned a highly polymorphic trinucleotide repeat consisting of (CTA)(n) (CTG)(n), which is very long (~1,800 bp) in this patient. The repeat region localizes to chromosome 13q21, within 1.2 cM of fragile site FRA13C. Repeat alleles in our sample were unstable in 13 (5.6%) of 231 meioses. Large alleles (>100 repeats) were observed in 14 (1.25%) of 1,120 patients with psychosis, borderline personality disorder, or juvenile- onset depression and in 5 (.7%) of 710 healthy controls. Very large alleles were also detected for Centre d'Etude Polymorphisme Humaine (CEPH) reference family 1334. This triplet expansion has recently been reported to be the cause of spinocerebellar ataxia type 8 (SCA8); however, none of our large alleles above the disease threshold occurred in individuals either affected by SCA or with known family history of SCA. The high frequency of large alleles at this locus is inconsistent with the much rarer occurrence of SCA8. Thus, it seems unlikely that expansion alone causes SCA8; other genetic mechanisms may be necessary to explain SCA8 etiology.

UR - http://www.scopus.com/inward/record.url?scp=0033939994&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033939994&partnerID=8YFLogxK

U2 - 10.1086/302803

DO - 10.1086/302803

M3 - Article

C2 - 10712198

AN - SCOPUS:0033939994

SN - 0002-9297

VL - 66

SP - 819

EP - 829

JO - American journal of human genetics

JF - American journal of human genetics

IS - 3

ER -

An unstable trinucleotide-repeat region on chromosome 13 implicated in spinocerebellar ataxia: A common expansion locus

Abstract

Funding

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this