TY - JOUR
T1 - Mutation in CATIP (C2orf62) causes oligoteratoasthenozoospermia by affecting actin dynamics
AU - Arafat, Maram
AU - Harlev, Avi
AU - Har-Vardi, Iris
AU - Levitas, Eliahu
AU - Priel, Tsvia
AU - Gershoni, Moran
AU - Searby, Charles
AU - Sheffield, Val C.
AU - Lunenfeld, Eitan
AU - Parvari, Ruti
N1 - Publisher Copyright:
© Author(s) (or their employer(s)) 2021.
PY - 2021/2/1
Y1 - 2021/2/1
N2 - Background: Oligoteratoasthenozoospermia (OTA) combines deteriorated quantity, morphology and motility of the sperm, resulting in male factor infertility. Methods: We used whole genome genotyping and exome sequencing to identify the mutation causing OTA in four men in a consanguineous Bedouin family. We expressed the normal and mutated proteins tagged with c-Myc at the carboxy termini by transfection with pCDNA3.1 plasmid constructs to evaluate the effects on protein stability in HEK293 cells and on the kinetics of actin repolymerisation in retinal pigment epithelium cells. Patients' sperm samples were visualised by transmission electron microscopy to determine axoneme structures and were stained with fluorescent phalloidin to visualise the fibrillar (F)-actin. Results: A homozygous missense mutation in Ciliogenesis Associated TTC17 Interacting Protein (CATIP): c. T103A, p. Phe35Ile, a gene encoding a protein important in actin organisation and ciliogenesis, was identified as the causative mutation with a LOD score of 3.25. The mutation reduces the protein stability compared with the normal protein. Furthermore, overexpression of the normal protein, but not the mutated protein, inhibits repolymerisation of actin after disruption with cytochalasin D. A high percentage of spermatozoa axonemes from patients have abnormalities, as well as disturbances in the distribution of F-actin. Conclusion: This is the first report of a recessive mutation in CATIP in humans. The identified mutation may contribute to asthenozoospermia by its involvement in actin polymerisation and on the actin cytoskeleton. A mouse knockout homozygote for CATIP was reported to demonstrate male infertility as the sole phenotype.
AB - Background: Oligoteratoasthenozoospermia (OTA) combines deteriorated quantity, morphology and motility of the sperm, resulting in male factor infertility. Methods: We used whole genome genotyping and exome sequencing to identify the mutation causing OTA in four men in a consanguineous Bedouin family. We expressed the normal and mutated proteins tagged with c-Myc at the carboxy termini by transfection with pCDNA3.1 plasmid constructs to evaluate the effects on protein stability in HEK293 cells and on the kinetics of actin repolymerisation in retinal pigment epithelium cells. Patients' sperm samples were visualised by transmission electron microscopy to determine axoneme structures and were stained with fluorescent phalloidin to visualise the fibrillar (F)-actin. Results: A homozygous missense mutation in Ciliogenesis Associated TTC17 Interacting Protein (CATIP): c. T103A, p. Phe35Ile, a gene encoding a protein important in actin organisation and ciliogenesis, was identified as the causative mutation with a LOD score of 3.25. The mutation reduces the protein stability compared with the normal protein. Furthermore, overexpression of the normal protein, but not the mutated protein, inhibits repolymerisation of actin after disruption with cytochalasin D. A high percentage of spermatozoa axonemes from patients have abnormalities, as well as disturbances in the distribution of F-actin. Conclusion: This is the first report of a recessive mutation in CATIP in humans. The identified mutation may contribute to asthenozoospermia by its involvement in actin polymerisation and on the actin cytoskeleton. A mouse knockout homozygote for CATIP was reported to demonstrate male infertility as the sole phenotype.
KW - genome-wide
KW - linkage
KW - molecular genetics
UR - http://www.scopus.com/inward/record.url?scp=85086117811&partnerID=8YFLogxK
U2 - 10.1136/jmedgenet-2019-106825
DO - 10.1136/jmedgenet-2019-106825
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C2 - 32503832
AN - SCOPUS:85086117811
SN - 0022-2593
VL - 58
SP - 106
EP - 115
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
IS - 2
ER -