RESUMO
Globozoospermia is a rare phenotype of primary male infertility inducing the production of round-headed spermatozoa without acrosome. Anomalies of DPY19L2 account for 50-70% of all cases and the entire deletion of the gene is by far the most frequent defect identified. Here, we present a large cohort of 69 patients with 20-100% of globozoospermia. Genetic analyses including multiplex ligation-dependent probe amplification, Sanger sequencing and whole-exome sequencing identified 25 subjects with a homozygous DPY19L2 deletion (36%) and 14 carrying other DPY19L2 defects (20%). Overall, 11 deleterious single-nucleotide variants were identified including eight novel and three already published mutations. Patients with a higher rate of round-headed spermatozoa were more often diagnosed and had a higher proportion of loss of function anomalies, highlighting a good genotype phenotype correlation. No gene defects were identified in patients carrying < 50% of globozoospermia while diagnosis efficiency rose to 77% for patients with > 50% of globozoospermia. In addition, results from whole-exome sequencing were scrutinized for 23 patients with a DPY19L2 negative diagnosis, searching for deleterious variants in the nine other genes described to be associated with globozoospermia in human (C2CD6, C7orf61, CCDC62, CCIN, DNAH17, GGN, PICK1, SPATA16, and ZPBP1). Only one homozygous novel truncating variant was identified in the GGN gene in one patient, confirming the association of GGN with globozoospermia. In view of these results, we propose a novel diagnostic strategy focusing on patients with at least 50% of globozoospermia and based on a classical qualitative PCR to detect DPY19L2 homozygous deletions. In the absence of the latter, we recommend to perform whole-exome sequencing to search for defects in DPY19L2 as well as in the other previously described candidate genes.
Assuntos
Infertilidade Masculina/genética , Proteínas de Membrana/genética , Teratozoospermia/genética , Hormônios Testiculares/genética , Estudos de Coortes , Deleção de Genes , Estudos de Associação Genética/métodos , Testes Genéticos/métodos , Homozigoto , Humanos , Masculino , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , Espermatozoides/anormalidades , Sequenciamento do Exoma/métodosRESUMO
BACKGROUND: We investigated the long-term effects of continuous subcutaneous insulin infusion (CSII) on glucose control and microvascular complications in patients with type 1 diabetes (T1D). METHODS: A total of 157 patients (59 M/98 W; age 39.1 ± 14.8 years) with T1D who switched from multiple daily injections to CSII and used CSII for at least one year were included. HbA1c levels and status of microvascular complications before and while under CSII were analyzed, retrospectively. RESULTS: The follow-up period was 4.0 ± 1.5 years. HbA1c significantly decreased from 8.4 ± 1.3 to 7.7 ± 1.3% (68 ± 14 to 61 ± 14 mmol/mol) after 1-year CSII and remained lower than pre-CSII levels during four years. Patients with pre-CSII HbA1c >8.0% (64 mmol/mol) showed significant improvement of HbA1c for four years, while those with pre-CSII HbA1c <8.0% showed no significant change. The prevalence of retinopathy, albuminuria, and chronic kidney disease (CKD) were respectively 39%, 12%, and 9% at CSII initiation. During follow-up, the incidence of retinopathy, albuminuria, and CKD were 3.6, 2.5 and 1.4/100 patient-years. Onset or progression of retinopathy occurred in 16 (27.1%) patients with diabetes duration >15 years, and in three (4.3%) patients with diabetes duration <15 years ( P < .01). CONCLUSION: CSII was effective in improving HbA1c for up to four years, specifically in patients with HbA1c >8% (64 mmol/mol) prior to CSII. Incidence and progression rates of retinopathy and albuminuria were low, particularly in patients with a diabetes duration <15 years at CSII initiation. These results argue for not delaying a proposal of CSII initiation in T1D with sustained HbA1c >8% (64 mmol/mol).