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A Common Protamine 1 Promoter Polymorphism (–190 CA) Correlates With Abnormal Sperm Morphology and Increased Protamine P1/P2 Ratio in Infertile Patients

JOSÉ LUIS BALLESCÀ

From the ^* Human Genetics Research Group, IDIBAPS, Faculty of Medicine, University of Barcelona and Genetics and Biochemistry Service, Hospital Clínic i Provincial, and the Institut Clínic de Ginecologia, Obstetricia i Neonatologia, Hospital Clínic i Provincial, Barcelona, Spain.

Correspondence to: Dr Rafael Oliva, Human Genetics Research Group, IDIBAPS, Faculty of Medicine, University of Barcelona, Casanova 143, 08036, Barcelona, Spain (e-mail: roliva{at}ub.edu).

It is known that targeting the protamine 1 gene in mice leads to infertility, abnormal chromatin packaging, and abnormal sperm morphology. Because many infertile patients also have an abnormal sperm morphology and chromatin packaging, the human protamine 1 gene (PRM1) is an important candidate to screen for potential mutations. In this work, we have screened the PRM1 gene in search of potential mutations and determined the sperm morphology and the ratio between protamine 1 and protamine 2 (P1/P2 ratio). Direct sequencing of the PRM1 promoter led to the identification of a common single-nucleotide polymorphism (SNP; –190 CA). The –190 AA genotype was detected at a higher frequency (13.8%) in patients with markedly altered sperm morphology (9% normal forms) compared with other patients (4.5%; P < .05) or compared with controls (2.97%; P < .005). The allelic frequency of the PRM1 –190 CA change was also consistently higher (.331) in infertile patients with a markedly altered morphology compared with population controls (.178; P < .01). Additionally, we have determined that the P1/P2 ratio is significantly increased in patients with the PRM1 –190 AA genotype compared with patients with the CA or CC genotypes (P = .006, Mann-Whitney). These findings indicate that the common PRM1 –190 CA polymorphism identified is associated with abnormal sperm head morphology and abnormal P1/P2 ratio in infertile patients.

     Key words: Haplotype block, infertility, sperm, reproductive genetics, risk factor