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Loss-of-function mutations TDRD7 lead to a rare novel syndrome combining congenital cataract and non-obstructive azoospermia in humans

ABSTRACT: Purpose: Comorbid familial non-obstructive azoospermia (NOA) and congenital cataract (CC) has not been reported previously, and no single human gene has been associated with both diseases in humans. Our purpose is to uncover novel human mutations and genes causing familial NOA and CC. Methods: We performed whole-exome sequencing for two brothers with both NOA and CC from a consanguineous family.The proband was also carried out SNP array analysis. Mutation screening of TDRD7 was performed in another similar consanguineous family and 176 patients with azoospermia or CC alone and 520 healthy controls. Histological analysis was performed for the biopsied testicle sample in one patient, and knockout mice were constructed to verify the phenotype of the mutation in TDRD7. Results: Two novel loss-of-function mutations (c.324_325insA (T110Nfs*30) and (c.688-689insA (p.Y230X), respectively) of TDRD7 were found in the affected patients from the two unrelated consanguineous families. Histological analysis demonstrated a lack of mature sperm in the male patient’s seminiferous tubules. The mutations were not detected in patients with CC or NOA alone. Mice with Tdrd7 gene disrupted at a similar position precisely replicated the human syndrome. Conclusions: We identified TDRD7 causing CC as a new pathogenic gene for male azoospermia in human, with an autosomal recessive mode of inheritance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE100019 | GEO | 2017/06/15

SECONDARY ACCESSION(S): PRJNA390493

REPOSITORIES: GEO

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Project description:Infertility affects about one in six couples attempting pregnancy, with the man responsible in approximately half of the cases. Because the pathophysiology underlying azoospermia is not elucidated, most male infertility is diagnosed as idiopathic. Genome-wide gene expression analyses with microarray on testis specimens from 47 non-obstructive azoospermia (NOA) and 11 obstructive azoospermia (OA) patients were performed, and 2,611 transcripts that preferentially included genes relevant to gametogenesis and reproduction according to Gene Ontology classification were found to be differentially expressed. Using a set of 945 of the 2,611 transcripts without missing data, NOA was further categorized into three classes using the non-negative matrix factorization method. These three subclasses showed differences in Johnsenâs score, FSH level, and LH level. In addition, the 52 genes showing high statistical difference between NOA subclasses (P < 0.01 with Tukey's post hoc test) were subjected to allelic association analyses to identify genetic susceptibilities in 442 NOA patients and 475 fertile men. After two rounds of screening, SNPs of the ADP-ribosyltransferase 3 (ART3) gene were associated with NOA with highest significance with ART3-SNP25 (rs6836703; P = 0.0025). Haplotypes with 5 SNPs were constructed, and the most common haplotype was found to be under-represented in patients (NOA 26.6 % versus control 35.3 %, P = 0.000073). Subjects having the most common haplotype showed an elevated level of testosterone, suggesting a protective effect of the haplotype on spermatogenesis. Thus, genome-wide gene expression analyses were used to identify genes involved in the pathogenesis of NOA, and ART3 was subsequently identified as a susceptibility gene for NOA. These findings clarify the molecular pathophysiology of NOA and suggest a novel therapeutic target in the treatment of NOA. Experiment Overall Design: Comparative analysis of two disease phenotypes, using testicular biopsy specimens from 47 NOA and 11 OA patients. No experimental replicates.

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Loss-of-function mutations TDRD7 lead to a rare novel syndrome combining congenital cataract and non-obstructive azoospermia in humans

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