Germ cell arrest associated with a SETX mutation in ataxia oculomotor apraxia type 2

Sarah Rosanna Catford, Moira Kathleen O'Bryan, Robert Ian McLachlan, Martin Delatycki, Luk Rombauts

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Ataxia with oculomotor apraxia type 2 (AOA2) is a rare autosomal recessive neurodegenerative disorder characterized by cerebellar atrophy, peripheral neuropathy and oculomotor apraxia. It is caused by mutations in the SETX gene that encodes senataxin, a ubiquitously expressed protein that mediates processes, including transcription, transcription termination, DNA repair, RNA processing, DNA–RNA hybrid (R-loop) elimination and telomere stability. In mice, senataxin is essential for male germ cell development and fertility through its role in meiotic recombination and sex chromosome inactivation. AOA2 is associated with hypogonadism in women, but there are no reports of hypogonadism or infertility in men. We describe the first case of human male infertility caused by germ cell arrest in a man with AOA2. Our patient has a homozygous mutation in the SETX gene (NC_000009.11:g.135158775dup), which results in a frameshift and premature protein termination (NM_015046.6:c.6422dup, p.[Ser2142Glufs*23]). In accordance with the murine phenotype, testis histology revealed disrupted seminiferous tubules with spermatogonia and primary spermatocytes, but absent spermatids. Collectively, these data support an essential role of senataxin in human spermatogenesis, and provide a compelling case that men with AOA2 should be counselled at diagnosis about the possibility of infertility.

Original languageEnglish
Number of pages5
JournalReproductive BioMedicine Online
DOIs
Publication statusAccepted/In press - 1 Jan 2019

Keywords

  • Ataxia oculomotor apraxia type 2
  • Germ cell arrest
  • Male infertility
  • Non-obstructive azoospermia
  • Senataxin
  • SETX

Cite this

@article{3315f491bc5941ea82ebf4e17532abad,
title = "Germ cell arrest associated with a SETX mutation in ataxia oculomotor apraxia type 2",
abstract = "Ataxia with oculomotor apraxia type 2 (AOA2) is a rare autosomal recessive neurodegenerative disorder characterized by cerebellar atrophy, peripheral neuropathy and oculomotor apraxia. It is caused by mutations in the SETX gene that encodes senataxin, a ubiquitously expressed protein that mediates processes, including transcription, transcription termination, DNA repair, RNA processing, DNA–RNA hybrid (R-loop) elimination and telomere stability. In mice, senataxin is essential for male germ cell development and fertility through its role in meiotic recombination and sex chromosome inactivation. AOA2 is associated with hypogonadism in women, but there are no reports of hypogonadism or infertility in men. We describe the first case of human male infertility caused by germ cell arrest in a man with AOA2. Our patient has a homozygous mutation in the SETX gene (NC_000009.11:g.135158775dup), which results in a frameshift and premature protein termination (NM_015046.6:c.6422dup, p.[Ser2142Glufs*23]). In accordance with the murine phenotype, testis histology revealed disrupted seminiferous tubules with spermatogonia and primary spermatocytes, but absent spermatids. Collectively, these data support an essential role of senataxin in human spermatogenesis, and provide a compelling case that men with AOA2 should be counselled at diagnosis about the possibility of infertility.",
keywords = "Ataxia oculomotor apraxia type 2, Germ cell arrest, Male infertility, Non-obstructive azoospermia, Senataxin, SETX",
author = "Catford, {Sarah Rosanna} and O'Bryan, {Moira Kathleen} and McLachlan, {Robert Ian} and Martin Delatycki and Luk Rombauts",
year = "2019",
month = "1",
day = "1",
doi = "10.1016/j.rbmo.2018.12.042",
language = "English",
journal = "Reproductive BioMedicine Online",
issn = "1472-6483",
publisher = "Elsevier",

}

Germ cell arrest associated with a SETX mutation in ataxia oculomotor apraxia type 2. / Catford, Sarah Rosanna; O'Bryan, Moira Kathleen; McLachlan, Robert Ian; Delatycki, Martin; Rombauts, Luk.

In: Reproductive BioMedicine Online, 01.01.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Germ cell arrest associated with a SETX mutation in ataxia oculomotor apraxia type 2

AU - Catford, Sarah Rosanna

AU - O'Bryan, Moira Kathleen

AU - McLachlan, Robert Ian

AU - Delatycki, Martin

AU - Rombauts, Luk

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Ataxia with oculomotor apraxia type 2 (AOA2) is a rare autosomal recessive neurodegenerative disorder characterized by cerebellar atrophy, peripheral neuropathy and oculomotor apraxia. It is caused by mutations in the SETX gene that encodes senataxin, a ubiquitously expressed protein that mediates processes, including transcription, transcription termination, DNA repair, RNA processing, DNA–RNA hybrid (R-loop) elimination and telomere stability. In mice, senataxin is essential for male germ cell development and fertility through its role in meiotic recombination and sex chromosome inactivation. AOA2 is associated with hypogonadism in women, but there are no reports of hypogonadism or infertility in men. We describe the first case of human male infertility caused by germ cell arrest in a man with AOA2. Our patient has a homozygous mutation in the SETX gene (NC_000009.11:g.135158775dup), which results in a frameshift and premature protein termination (NM_015046.6:c.6422dup, p.[Ser2142Glufs*23]). In accordance with the murine phenotype, testis histology revealed disrupted seminiferous tubules with spermatogonia and primary spermatocytes, but absent spermatids. Collectively, these data support an essential role of senataxin in human spermatogenesis, and provide a compelling case that men with AOA2 should be counselled at diagnosis about the possibility of infertility.

AB - Ataxia with oculomotor apraxia type 2 (AOA2) is a rare autosomal recessive neurodegenerative disorder characterized by cerebellar atrophy, peripheral neuropathy and oculomotor apraxia. It is caused by mutations in the SETX gene that encodes senataxin, a ubiquitously expressed protein that mediates processes, including transcription, transcription termination, DNA repair, RNA processing, DNA–RNA hybrid (R-loop) elimination and telomere stability. In mice, senataxin is essential for male germ cell development and fertility through its role in meiotic recombination and sex chromosome inactivation. AOA2 is associated with hypogonadism in women, but there are no reports of hypogonadism or infertility in men. We describe the first case of human male infertility caused by germ cell arrest in a man with AOA2. Our patient has a homozygous mutation in the SETX gene (NC_000009.11:g.135158775dup), which results in a frameshift and premature protein termination (NM_015046.6:c.6422dup, p.[Ser2142Glufs*23]). In accordance with the murine phenotype, testis histology revealed disrupted seminiferous tubules with spermatogonia and primary spermatocytes, but absent spermatids. Collectively, these data support an essential role of senataxin in human spermatogenesis, and provide a compelling case that men with AOA2 should be counselled at diagnosis about the possibility of infertility.

KW - Ataxia oculomotor apraxia type 2

KW - Germ cell arrest

KW - Male infertility

KW - Non-obstructive azoospermia

KW - Senataxin

KW - SETX

UR - http://www.scopus.com/inward/record.url?scp=85059781289&partnerID=8YFLogxK

U2 - 10.1016/j.rbmo.2018.12.042

DO - 10.1016/j.rbmo.2018.12.042

M3 - Article

JO - Reproductive BioMedicine Online

JF - Reproductive BioMedicine Online

SN - 1472-6483

ER -