Azoospermia in patients heterozygous for a mutation in SYCP3.
BACKGROUND
Many cases of male infertility are diagnosed as idiopathic, reflecting poor understanding of the molecular defects underlying the abnormality. As more gene mutations causing male infertility in mice become known, there are improving prospects that knowledge about the genetic aetiology of human male infertility can be expanded. Sycp3 encodes a component of the synaptonemal complex. A null mutation of Sycp3 in mice causes azoospermia with meiotic arrest. We tested the hypothesis that mutation of the human testis-specific SYCP3 is associated with human non-obstructive azoospermia.


METHODS
Human SYCP3 was isolated on the basis of homology between mouse Sycp3 cDNA and human genome sequences at the aminoacid level. Tissue-specific expression of SYCP3 was analysed by PCR of human cDNA. Samples of DNA from 19 azoospermic patients with maturation arrest and 75 normal fertile control men were screened for mutations in the SYCP3 gene by sequence analysis of the gene. The functional significance of the mutations found was analysed by a protein interaction study of the wild-type and truncated SYCP3 proteins.


RESULTS
We identified in two patients a 1 bp deletion (643delA) that results in a premature stop codon and truncation of the C-terminal, coiled-coil-forming region of the SYCP3 protein. The mutant protein showed greatly reduced interaction with the wild-type protein in vitro and interfered with SYCP3 fibre formation in cultured cells.


CONCLUSIONS
We suggest that SYCP3 has an essential meiotic function in human spermatogenesis that is compromised by the mutant protein via dominant negative interference.
Miyamoto
Toshinobu
T
Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
Hasuike
Shiga
S
Yogev
Leah
L
Maduro
Maria R
MR
Ishikawa
Mutsuo
M
Westphal
Heiner
H
Lamb
Dolores J
DJ
D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins; D002881:Chromosomes, Human, Pair 12; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D006579:Heterozygote; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000235:genetics*; D009845:Oligospermia / Q000235:genetics* / Q000473:pathology; D017384:Sequence Deletion; D013573:Synaptonemal Complex / Q000235:genetics; D013737:Testis / Q000473:pathology
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C490060:SYCP3 protein, human; C490062:Sycp3 protein, mouse