SYCP2 Translocation-Mediated Dysregulation and Frameshift Variants Cause Human Male Infertility.
Am J Hum Genet
; 106(1): 41-57, 2020 01 02.
Article
em En
| MEDLINE
| ID: mdl-31866047
ABSTRACT
Unexplained infertility affects 2%-3% of reproductive-aged couples. One approach to identifying genes involved in infertility is to study subjects with this clinical phenotype and a de novo balanced chromosomal aberration (BCA). While BCAs may reduce fertility by production of unbalanced gametes, a chromosomal rearrangement may also disrupt or dysregulate genes important in fertility. One such subject, DGAP230, has severe oligozoospermia and 46,XY,t(20;22)(q13.3;q11.2). We identified exclusive overexpression of SYCP2 from the der(20) allele that is hypothesized to result from enhancer adoption. Modeling the dysregulation in budding yeast resulted in disrupted structural integrity of the synaptonemal complex, a common cause of defective spermatogenesis in mammals. Exome sequencing of infertile males revealed three heterozygous SYCP2 frameshift variants in additional subjects with cryptozoospermia and azoospermia. In sum, this investigation illustrates the power of precision cytogenetics for annotation of the infertile genome, suggests that these mechanisms should be considered as an alternative etiology to that of segregation of unbalanced gametes in infertile men harboring a BCA, and provides evidence of SYCP2-mediated male infertility in humans.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Oligospermia
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Mutação da Fase de Leitura
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Aberrações Cromossômicas
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Proteínas de Ciclo Celular
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Proteínas de Ligação a DNA
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Infertilidade Masculina
Limite:
Adult
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article