Homozygous in-frame deletion in CATSPERE in a man producing spermatozoa with loss of CatSper function and compromised fertilizing capacity

Sean G. Brown, Melissa R. Miller, Polina V. Lishko, Douglas H. Lester, Stephen J. Publicover, Christopher L. R. Barratt (Lead / Corresponding author), Sarah Martins Da Silva

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Abstract

Study question: Does a man (patient 1) with a previously described deficiency in principle cation channel of sperm (CatSper) function have a mutation in the CatSper-epsilon (CATSPERE) and/or CatSper-zeta (CATSPERZ) gene?

Summary answer: Patient 1 has a homozygous in-frame 6-bp deletion in exon 18 (c.2393-2398delCTATGG, rs761237686) of CATSPERE. WHAT IS KNOWN ALREADY: CatSper is the principal calcium channel of mammalian spermatozoa. Spermatozoa from patient 1 had a specific loss of CatSper function and were unable to fertilize at IVF. Loss of CatSper function could not be attributed to genetic abnormalities in coding regions of seven CatSper subunits. Two additional subunits (CatSper-epsilon (CATPSERE) and CatSper-zeta (CATSPERZ)) were recently identified, and are now proposed to contribute to the formation of the mature channel complex. STUDY DESIGN, SIZE, DURATION: This was a basic medical research study analysing genomic data from a single patient (patient 1) for defects in CATSPERE and CATSPERZ.

Participants/materials, setting, methods: The original exome sequencing data for patient 1 were analysed for mutations in CATSPERE and CATSPERZ. Sanger sequencing was conducted to confirm the presence of a rare variant.

Main results and the role of chance: Patient 1 is homozygous for an in-frame 6-bp deletion in exon 18 (c.2393-2398delCTATGG, rs761237686) of CATSPERE that is predicted to be highly deleterious.

Limitations, reasons for caution: The nature of the molecular deficit caused by the rs761237686 variant and whether it is exclusively responsible for the loss of CatSper function remain to be elucidated.

Wider implications of the findings: Population genetics are available for a significant number of predicted deleterious variants of CatSper subunits. The consequence of homozygous and compound heterozygous forms on sperm fertilization potential could be significant. Selective targeting of CatSper subunit expression maybe a feasible strategy for the development of novel contraceptives.

Original languageEnglish
Pages (from-to)1812-1816
Number of pages5
JournalHuman Reproduction
Volume33
Issue number10
Early online date17 Sep 2018
DOIs
Publication statusPublished - 1 Oct 2018

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Spermatozoa
Cations
Exons
Exome
Mutation
Population Genetics
Calcium Channels
Contraceptive Agents
Fertilization
Biomedical Research

Keywords

  • Calcium signaling
  • CatSper
  • Infertility
  • Mutation
  • Spermatozoa

Cite this

Brown, Sean G. ; Miller, Melissa R. ; Lishko, Polina V. ; Lester, Douglas H. ; Publicover, Stephen J. ; Barratt, Christopher L. R. ; Martins Da Silva, Sarah. / Homozygous in-frame deletion in CATSPERE in a man producing spermatozoa with loss of CatSper function and compromised fertilizing capacity. In: Human Reproduction. 2018 ; Vol. 33, No. 10. pp. 1812-1816.
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abstract = "Study question: Does a man (patient 1) with a previously described deficiency in principle cation channel of sperm (CatSper) function have a mutation in the CatSper-epsilon (CATSPERE) and/or CatSper-zeta (CATSPERZ) gene?Summary answer: Patient 1 has a homozygous in-frame 6-bp deletion in exon 18 (c.2393-2398delCTATGG, rs761237686) of CATSPERE. WHAT IS KNOWN ALREADY: CatSper is the principal calcium channel of mammalian spermatozoa. Spermatozoa from patient 1 had a specific loss of CatSper function and were unable to fertilize at IVF. Loss of CatSper function could not be attributed to genetic abnormalities in coding regions of seven CatSper subunits. Two additional subunits (CatSper-epsilon (CATPSERE) and CatSper-zeta (CATSPERZ)) were recently identified, and are now proposed to contribute to the formation of the mature channel complex. STUDY DESIGN, SIZE, DURATION: This was a basic medical research study analysing genomic data from a single patient (patient 1) for defects in CATSPERE and CATSPERZ.Participants/materials, setting, methods: The original exome sequencing data for patient 1 were analysed for mutations in CATSPERE and CATSPERZ. Sanger sequencing was conducted to confirm the presence of a rare variant.Main results and the role of chance: Patient 1 is homozygous for an in-frame 6-bp deletion in exon 18 (c.2393-2398delCTATGG, rs761237686) of CATSPERE that is predicted to be highly deleterious.Limitations, reasons for caution: The nature of the molecular deficit caused by the rs761237686 variant and whether it is exclusively responsible for the loss of CatSper function remain to be elucidated.Wider implications of the findings: Population genetics are available for a significant number of predicted deleterious variants of CatSper subunits. The consequence of homozygous and compound heterozygous forms on sperm fertilization potential could be significant. Selective targeting of CatSper subunit expression maybe a feasible strategy for the development of novel contraceptives.",
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Homozygous in-frame deletion in CATSPERE in a man producing spermatozoa with loss of CatSper function and compromised fertilizing capacity. / Brown, Sean G.; Miller, Melissa R.; Lishko, Polina V.; Lester, Douglas H.; Publicover, Stephen J.; Barratt, Christopher L. R. (Lead / Corresponding author); Martins Da Silva, Sarah.

In: Human Reproduction, Vol. 33, No. 10, 01.10.2018, p. 1812-1816.

Research output: Contribution to journalArticle

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T1 - Homozygous in-frame deletion in CATSPERE in a man producing spermatozoa with loss of CatSper function and compromised fertilizing capacity

AU - Brown, Sean G.

AU - Miller, Melissa R.

AU - Lishko, Polina V.

AU - Lester, Douglas H.

AU - Publicover, Stephen J.

AU - Barratt, Christopher L. R.

AU - Martins Da Silva, Sarah

N1 - Project grants from the MRC (MR/K013343/1 and MR/012492/1) (S.G.B., S.J.P., C.L.R.B.), Tenovus Scotland and Chief Scientist Office/NHS research Scotland (S.M.S.S.) and NIH R01GM111802, Pew Biomedical Scholars Award 00028642 and Packer Wentz Endowment Will to P.V.L.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - Study question: Does a man (patient 1) with a previously described deficiency in principle cation channel of sperm (CatSper) function have a mutation in the CatSper-epsilon (CATSPERE) and/or CatSper-zeta (CATSPERZ) gene?Summary answer: Patient 1 has a homozygous in-frame 6-bp deletion in exon 18 (c.2393-2398delCTATGG, rs761237686) of CATSPERE. WHAT IS KNOWN ALREADY: CatSper is the principal calcium channel of mammalian spermatozoa. Spermatozoa from patient 1 had a specific loss of CatSper function and were unable to fertilize at IVF. Loss of CatSper function could not be attributed to genetic abnormalities in coding regions of seven CatSper subunits. Two additional subunits (CatSper-epsilon (CATPSERE) and CatSper-zeta (CATSPERZ)) were recently identified, and are now proposed to contribute to the formation of the mature channel complex. STUDY DESIGN, SIZE, DURATION: This was a basic medical research study analysing genomic data from a single patient (patient 1) for defects in CATSPERE and CATSPERZ.Participants/materials, setting, methods: The original exome sequencing data for patient 1 were analysed for mutations in CATSPERE and CATSPERZ. Sanger sequencing was conducted to confirm the presence of a rare variant.Main results and the role of chance: Patient 1 is homozygous for an in-frame 6-bp deletion in exon 18 (c.2393-2398delCTATGG, rs761237686) of CATSPERE that is predicted to be highly deleterious.Limitations, reasons for caution: The nature of the molecular deficit caused by the rs761237686 variant and whether it is exclusively responsible for the loss of CatSper function remain to be elucidated.Wider implications of the findings: Population genetics are available for a significant number of predicted deleterious variants of CatSper subunits. The consequence of homozygous and compound heterozygous forms on sperm fertilization potential could be significant. Selective targeting of CatSper subunit expression maybe a feasible strategy for the development of novel contraceptives.

AB - Study question: Does a man (patient 1) with a previously described deficiency in principle cation channel of sperm (CatSper) function have a mutation in the CatSper-epsilon (CATSPERE) and/or CatSper-zeta (CATSPERZ) gene?Summary answer: Patient 1 has a homozygous in-frame 6-bp deletion in exon 18 (c.2393-2398delCTATGG, rs761237686) of CATSPERE. WHAT IS KNOWN ALREADY: CatSper is the principal calcium channel of mammalian spermatozoa. Spermatozoa from patient 1 had a specific loss of CatSper function and were unable to fertilize at IVF. Loss of CatSper function could not be attributed to genetic abnormalities in coding regions of seven CatSper subunits. Two additional subunits (CatSper-epsilon (CATPSERE) and CatSper-zeta (CATSPERZ)) were recently identified, and are now proposed to contribute to the formation of the mature channel complex. STUDY DESIGN, SIZE, DURATION: This was a basic medical research study analysing genomic data from a single patient (patient 1) for defects in CATSPERE and CATSPERZ.Participants/materials, setting, methods: The original exome sequencing data for patient 1 were analysed for mutations in CATSPERE and CATSPERZ. Sanger sequencing was conducted to confirm the presence of a rare variant.Main results and the role of chance: Patient 1 is homozygous for an in-frame 6-bp deletion in exon 18 (c.2393-2398delCTATGG, rs761237686) of CATSPERE that is predicted to be highly deleterious.Limitations, reasons for caution: The nature of the molecular deficit caused by the rs761237686 variant and whether it is exclusively responsible for the loss of CatSper function remain to be elucidated.Wider implications of the findings: Population genetics are available for a significant number of predicted deleterious variants of CatSper subunits. The consequence of homozygous and compound heterozygous forms on sperm fertilization potential could be significant. Selective targeting of CatSper subunit expression maybe a feasible strategy for the development of novel contraceptives.

KW - Calcium signaling

KW - CatSper

KW - Infertility

KW - Mutation

KW - Spermatozoa

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