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

Abstract

PurposeComorbid familial nonobstructive azoospermia (NOA) and congenital cataract (CC) have not been reported previously, and no single human gene has been associated with both diseases in humans. Our purpose was to uncover novel human mutations and genes causing familial NOA and CC.MethodsWe performed whole-exome sequencing for two brothers with both NOA and CC from a consanguineous family. 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.ResultsTwo 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.ConclusionWe identified TDRD7 causing CC as a new pathogenic gene for male azoospermia in human, with an autosomal recessive mode of inheritance.GENETICS in MEDICINE advance online publication, 24 August 2017; doi:10.1038/gim.2017.130.

Novel inactivating mutations in the FSH receptor cause premature ovarian insufficiency with resistant ovary syndrome

“…Genomic DNA (gDNA) from peripheral blood samples was extracted using a QIAamp® DNA Blood Midi Kit (Qiagen; Hilden, Germany). The 13 probands were subjected to WES using the HiSeq2000 sequencing platform (Illumina Inc., San Diego, CA, USA) at the Beijing Genome Institute at Shenzhen, as described previously (He et al, 2017;Tan et al, 2017;Zhu et al, 2016). WES data analysis was performed using the Genome Analysis Toolkit (GATK; https://software.…”

The Tudor-domain protein TDRD7, mutated in congenital cataract, controls the heat shock protein HSPB1 (HSP27) and lens fiber cell morphology

“…We recently reported that mutations in the ribonucleoprotein/RNA granule component gene TDRD7 (OMIM: 611258) cause congenital cataracts, suggesting that regulators of post-transcriptional gene expression control have key function in vertebrate lens development and maintenance of transparency ( 17–21 ). Subsequent to our report, new human mutations in TDRD7 have been linked to cataract in independent studies ( 22 , 23 ). Moreover, a TDRD7 polymorphism has been associated with age-related cataracts in a Han Chinese population ( 24 ), and expression profiling analyses have demonstrated a significant downregulation of TDRD7 transcripts in human aged cataractous lenses ( 25 ), providing further evidence for the importance of this gene in lens development and homeostasis.…”

An M1AP homozygous splice‐site mutation associated with severe oligozoospermia in a consanguineous family

“…In total, 138,085 variants were detected in the affected individual. The most promising candidate variants were identified using criteria described in our previous studies . Briefly, candidate variants were considered a priority when they met the following criteria: frequency below 5% in three public databases; predicted to be deleterious; homozygous; and relevance to infertility phenotypes.…”

“…We performed targeted look‐up for M1AP variants in 243 subjects with SO and 223 subjects with normal fertility, described in our previous study . Subsequently, genomic DNA samples were subjected to WES as previously described, followed by Sanger sequencing. Reverse transcription polymerase chain reaction (RT‐PCR) and immunoblotting analyses were used to verify pathogenicity.…”