Characterization of the c9orf72 GC-rich low complexity sequence in two cohorts of Italian and Turkish ALS cases

Lucia Corrado, Cinzia Tiloca, Clarissa Locci, Alessandra Bagarotti, Hamid Hamzeiy, Claudia Colombrita, Fabiola De marchi, Nadia Barizzone, Diego Cotella, Nicola Ticozzi, Letizia Mazzini, A. Y.S.E. Nazli Basak, Antonia Ratti, Vincenzo Silani, Sandra D’alfonso

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Large expansions of a noncoding GGGGCC repeat in the C9orf72 gene are the main cause of amyotrophic lateral sclerosis (ALS). The GGGGCC repeat is contiguous with another GC-rich region. Recent studies reported a significantly higher frequency of insertions/deletions within the GC-rich region in patients carrying the GGGGCC expansion. A GTGGT motif comprised within the GC-rich region, which joins two 100% GC sequences, was frequently deleted, supporting the hypothesis that these deletions could make the region more prone to slippage and pathological expansion. To confirm this hypothesis, we sequenced the GC-rich region adjacent the GGGGCC repeat in ALS patients, 116 C9orf72 expansion carriers, 219 non-carriers, and 223 healthy controls, from Italian and Turkish cohorts. Deletions were significantly more frequent in C9orf72 expansion carriers (6%) compared to non-carrier ALS patients (0.46%, OR =14.00, 95% CI =1.71–306.59, p = 0.003), to controls (0%, OR =16.29, 95% CI =2.12–725.99, p = 4.86 × 10−4) and to the whole cohort of non-carriers (0.2%, OR =28.51, 95% CI =3.47–618.91, p = 9.58 × 10−5). Among expansion carriers, deletions with or without the GTGGT motif were equally distributed (4 vs. 3). The frequency of insertions was not statistically different between C9orf72 expansion carriers and any other group including the whole cohort of non-carriers (p = 0.439, Fisher’s exact test). Our data confirmed the association between deletions within GC-rich region and the GGGGCC expansion in Italian and Turkish cases, although we did not confirm a role of the GTGGT element deletion. Further studies will be therefore necessary to assess the causal relationships between contiguous deletions of the GC-rich region and the GGGGCC expansion.

Original languageEnglish
Pages (from-to)426-431
Number of pages6
JournalAmyotrophic Lateral Sclerosis and Frontotemporal Degeneration
Volume19
Issue number5-6
DOIs
Publication statusPublished - Jul 3 2018

Fingerprint

GC Rich Sequence
Amyotrophic Lateral Sclerosis
Genes

Keywords

  • ALS
  • C9orf72
  • deletion
  • indel
  • low complexity sequence
  • repeat

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Characterization of the c9orf72 GC-rich low complexity sequence in two cohorts of Italian and Turkish ALS cases. / Corrado, Lucia; Tiloca, Cinzia; Locci, Clarissa; Bagarotti, Alessandra; Hamzeiy, Hamid; Colombrita, Claudia; De marchi, Fabiola; Barizzone, Nadia; Cotella, Diego; Ticozzi, Nicola; Mazzini, Letizia; Nazli Basak, A. Y.S.E.; Ratti, Antonia; Silani, Vincenzo; D’alfonso, Sandra.

In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, Vol. 19, No. 5-6, 03.07.2018, p. 426-431.

Research output: Contribution to journalArticle

Corrado, Lucia ; Tiloca, Cinzia ; Locci, Clarissa ; Bagarotti, Alessandra ; Hamzeiy, Hamid ; Colombrita, Claudia ; De marchi, Fabiola ; Barizzone, Nadia ; Cotella, Diego ; Ticozzi, Nicola ; Mazzini, Letizia ; Nazli Basak, A. Y.S.E. ; Ratti, Antonia ; Silani, Vincenzo ; D’alfonso, Sandra. / Characterization of the c9orf72 GC-rich low complexity sequence in two cohorts of Italian and Turkish ALS cases. In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. 2018 ; Vol. 19, No. 5-6. pp. 426-431.
@article{653d72ea922c493a89d6ad2c20b552da,
title = "Characterization of the c9orf72 GC-rich low complexity sequence in two cohorts of Italian and Turkish ALS cases",
abstract = "Large expansions of a noncoding GGGGCC repeat in the C9orf72 gene are the main cause of amyotrophic lateral sclerosis (ALS). The GGGGCC repeat is contiguous with another GC-rich region. Recent studies reported a significantly higher frequency of insertions/deletions within the GC-rich region in patients carrying the GGGGCC expansion. A GTGGT motif comprised within the GC-rich region, which joins two 100{\%} GC sequences, was frequently deleted, supporting the hypothesis that these deletions could make the region more prone to slippage and pathological expansion. To confirm this hypothesis, we sequenced the GC-rich region adjacent the GGGGCC repeat in ALS patients, 116 C9orf72 expansion carriers, 219 non-carriers, and 223 healthy controls, from Italian and Turkish cohorts. Deletions were significantly more frequent in C9orf72 expansion carriers (6{\%}) compared to non-carrier ALS patients (0.46{\%}, OR =14.00, 95{\%} CI =1.71–306.59, p = 0.003), to controls (0{\%}, OR =16.29, 95{\%} CI =2.12–725.99, p = 4.86 × 10−4) and to the whole cohort of non-carriers (0.2{\%}, OR =28.51, 95{\%} CI =3.47–618.91, p = 9.58 × 10−5). Among expansion carriers, deletions with or without the GTGGT motif were equally distributed (4 vs. 3). The frequency of insertions was not statistically different between C9orf72 expansion carriers and any other group including the whole cohort of non-carriers (p = 0.439, Fisher’s exact test). Our data confirmed the association between deletions within GC-rich region and the GGGGCC expansion in Italian and Turkish cases, although we did not confirm a role of the GTGGT element deletion. Further studies will be therefore necessary to assess the causal relationships between contiguous deletions of the GC-rich region and the GGGGCC expansion.",
keywords = "ALS, C9orf72, deletion, indel, low complexity sequence, repeat",
author = "Lucia Corrado and Cinzia Tiloca and Clarissa Locci and Alessandra Bagarotti and Hamid Hamzeiy and Claudia Colombrita and {De marchi}, Fabiola and Nadia Barizzone and Diego Cotella and Nicola Ticozzi and Letizia Mazzini and {Nazli Basak}, {A. Y.S.E.} and Antonia Ratti and Vincenzo Silani and Sandra D’alfonso",
year = "2018",
month = "7",
day = "3",
doi = "10.1080/21678421.2018.1440407",
language = "English",
volume = "19",
pages = "426--431",
journal = "Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration",
issn = "2167-8421",
publisher = "Informa Healthcare",
number = "5-6",

}

TY - JOUR

T1 - Characterization of the c9orf72 GC-rich low complexity sequence in two cohorts of Italian and Turkish ALS cases

AU - Corrado, Lucia

AU - Tiloca, Cinzia

AU - Locci, Clarissa

AU - Bagarotti, Alessandra

AU - Hamzeiy, Hamid

AU - Colombrita, Claudia

AU - De marchi, Fabiola

AU - Barizzone, Nadia

AU - Cotella, Diego

AU - Ticozzi, Nicola

AU - Mazzini, Letizia

AU - Nazli Basak, A. Y.S.E.

AU - Ratti, Antonia

AU - Silani, Vincenzo

AU - D’alfonso, Sandra

PY - 2018/7/3

Y1 - 2018/7/3

N2 - Large expansions of a noncoding GGGGCC repeat in the C9orf72 gene are the main cause of amyotrophic lateral sclerosis (ALS). The GGGGCC repeat is contiguous with another GC-rich region. Recent studies reported a significantly higher frequency of insertions/deletions within the GC-rich region in patients carrying the GGGGCC expansion. A GTGGT motif comprised within the GC-rich region, which joins two 100% GC sequences, was frequently deleted, supporting the hypothesis that these deletions could make the region more prone to slippage and pathological expansion. To confirm this hypothesis, we sequenced the GC-rich region adjacent the GGGGCC repeat in ALS patients, 116 C9orf72 expansion carriers, 219 non-carriers, and 223 healthy controls, from Italian and Turkish cohorts. Deletions were significantly more frequent in C9orf72 expansion carriers (6%) compared to non-carrier ALS patients (0.46%, OR =14.00, 95% CI =1.71–306.59, p = 0.003), to controls (0%, OR =16.29, 95% CI =2.12–725.99, p = 4.86 × 10−4) and to the whole cohort of non-carriers (0.2%, OR =28.51, 95% CI =3.47–618.91, p = 9.58 × 10−5). Among expansion carriers, deletions with or without the GTGGT motif were equally distributed (4 vs. 3). The frequency of insertions was not statistically different between C9orf72 expansion carriers and any other group including the whole cohort of non-carriers (p = 0.439, Fisher’s exact test). Our data confirmed the association between deletions within GC-rich region and the GGGGCC expansion in Italian and Turkish cases, although we did not confirm a role of the GTGGT element deletion. Further studies will be therefore necessary to assess the causal relationships between contiguous deletions of the GC-rich region and the GGGGCC expansion.

AB - Large expansions of a noncoding GGGGCC repeat in the C9orf72 gene are the main cause of amyotrophic lateral sclerosis (ALS). The GGGGCC repeat is contiguous with another GC-rich region. Recent studies reported a significantly higher frequency of insertions/deletions within the GC-rich region in patients carrying the GGGGCC expansion. A GTGGT motif comprised within the GC-rich region, which joins two 100% GC sequences, was frequently deleted, supporting the hypothesis that these deletions could make the region more prone to slippage and pathological expansion. To confirm this hypothesis, we sequenced the GC-rich region adjacent the GGGGCC repeat in ALS patients, 116 C9orf72 expansion carriers, 219 non-carriers, and 223 healthy controls, from Italian and Turkish cohorts. Deletions were significantly more frequent in C9orf72 expansion carriers (6%) compared to non-carrier ALS patients (0.46%, OR =14.00, 95% CI =1.71–306.59, p = 0.003), to controls (0%, OR =16.29, 95% CI =2.12–725.99, p = 4.86 × 10−4) and to the whole cohort of non-carriers (0.2%, OR =28.51, 95% CI =3.47–618.91, p = 9.58 × 10−5). Among expansion carriers, deletions with or without the GTGGT motif were equally distributed (4 vs. 3). The frequency of insertions was not statistically different between C9orf72 expansion carriers and any other group including the whole cohort of non-carriers (p = 0.439, Fisher’s exact test). Our data confirmed the association between deletions within GC-rich region and the GGGGCC expansion in Italian and Turkish cases, although we did not confirm a role of the GTGGT element deletion. Further studies will be therefore necessary to assess the causal relationships between contiguous deletions of the GC-rich region and the GGGGCC expansion.

KW - ALS

KW - C9orf72

KW - deletion

KW - indel

KW - low complexity sequence

KW - repeat

UR - http://www.scopus.com/inward/record.url?scp=85042916340&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85042916340&partnerID=8YFLogxK

U2 - 10.1080/21678421.2018.1440407

DO - 10.1080/21678421.2018.1440407

M3 - Article

VL - 19

SP - 426

EP - 431

JO - Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

JF - Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

SN - 2167-8421

IS - 5-6

ER -