Novel Tu translation elongation factor, mitochondrial (TUFM) homozygous variant in a consanguineous family with premature ovarian insufficiency.

Premature ovarian insufficiency (POI) is a clinical syndrome of ovarian dysfunction characterized by cessation of menstruation occurring before the age of 40 years. The genetic causes of idiopathic POI remain unclear. Here we recruited a POI patient from a consanguineous family to screen for potential pathogenic variants associated with POI. Genetic variants of the pedigree were screened using whole-exome sequencing analysis and validated through direct Sanger sequencing. A homozygous variant in TUFM (c.524G>C: p.Gly175Ala) was identified in this family. TUFM (Tu translation elongation factor, mitochondrial) is a nuclear-encoded mitochondrial protein translation elongation factor that plays a critical role in maintaining normal mitochondrial function. The variant position was highly conserved among species and predicted to be disease causing. Our in vitro functional studies demonstrated that this variant causes decreased TUFM protein expression, leading to mitochondrial dysfunction and impaired autophagy activation. Moreover, we found that mice with targeted Tufm variant recapitulated the phenotypes of human POI. Thus, this is the first report of a homozygous pathogenic TUFM variant in POI. Our findings highlighted the essential role of mitochondrial genes in folliculogenesis and ovarian function maintenance.

The identification of AMZ2 as a candidate causative gene in a severe teratozoospermia patient characterized by vacuolated spermatozoa.

Teratozoospermia with cephalic defects is one of the most severe types of sperm defects known to date. While several monogenic factors are linked to cephalic abnormalities, such as globozoospermia and macrozoospermia, the genetic cause of vacuolated spermatozoa remains inadequately described. Here, we analyzed whole-exome sequencing (WES) data for an individual from a consanguineous family with severely vacuolated spermatozoa. The analysis revealed a novel homozygous c.520A>G (p.Thr174Ala) variant in the archaelysin family metallopeptidase 2 (AMZ2), a gene that encodes a zinc metalloprotease previously shown to be highly expressed in the testes and sperm. Multiple algorithms predicted this variant to be a damaging mutation. Consistent with an autosomal recessive mode of inheritance, this variant was inherited from heterozygous parental carriers. To investigate the potential pathogenicity of the identified variant, we compared the AMZ2 expression in sperm cells from the patient with the AMZ2 variant and from a healthy control. Immunoblot analysis revealed that the homozygous missense variant in AMZ2 abolished AMZ2 expression in the spermatozoa. Our findings reveal a candidate causative gene for vacuolated spermatozoa.

Whole exome sequencing and trio analysis to broaden the variant spectrum of genes in idiopathic hypogonadotropic hypogonadism.

Dozens of genes are associated with idiopathic hypogonadotropic hypogonadism (IHH) and an oligogenic etiology has been suggested. However, the associated genes may account for only approximately 50% cases. In addition, a genomic systematic pedigree analysis is still lacking. Here, we conducted whole exome sequencing (WES) on 18 unrelated men affected by IHH and their corresponding parents. Notably, one reported and 10 novel variants in eight known IHH causative genes (AXL, CCDC141, CHD7, DMXL2, FGFR1, PNPLA6, POLR3A, and PROKR2), nine variants in nine recently reported candidate genes (DCAF17, DCC, EGF, IGSF10, NOTCH1, PDE3A, RELN, SLIT2, and TRAPPC9), and four variants in four novel candidate genes for IHH (CCDC88C, CDON, GADL1, and SPRED3) were identified in 77.8% (14/18) of IHH cases. Among them, eight (8/18, 44.4%) cases carried more than one variant in IHH-related genes, supporting the oligogenic model. Interestingly, we found that those variants tended to be maternally inherited (maternal with n = 17 vs paternal with n = 7; P = 0.028). Our further retrospective investigation of published reports replicated the maternal bias (maternal with n = 46 vs paternal with n = 28; P = 0.024). Our study extended a variant spectrum for IHH and provided the first evidence that women are probably more tolerant to variants of IHH-related genes than men.

ANTI-DIABETIC EFFECTS OF ZHUODUQING FORMULA, A CHINESE HERBAL DECOCTION, ON A RAT MODEL OF TYPE 2 DIABETES.

BACKGROUND: Zhuoduqing formula (ZDQ) is a Chinese herbal decoction and used to treat type 2 diabetes in clinical practice, but the potential evidence needs to be provided. MATERIALS AND METHODS: Type 2 diabetic model rats were induced by feeding high fat diet (HFD) and intraperitoneal injection of streptozotocin (STZ). The model rats were given ZDQ for 4 weeks. Insulin sensitivity was evaluated by homeostasis model assessment of basal insulin resistance (HOMA-IR) and intraperitoneal glucose tolerance test (IPGTT). Blood insulin and tumour necrosis factor-α (TNF-α) levels as well as SOCS-3 levels in skeletal muscles were analyzed by ELISA. RESULTS: ZDQ significantly decreased fasting blood glucose, ameliorated HOMA-IR and IPGTT, and reduced triglyceride and total cholesterol in type 2 diabetic rats. Moreover, ZDQ remarkably lowered blood TNF-α levels and inhibited SOCS-3 levels in skeletal muscles. CONCLUSION: The results display that ZDQ performs anti-diabetic functions in type 2 diabetic rats induced by feeding HFD and intraperitoneal injection of STZ. Abbreviations: ZDQ, zhuoduqing formula; ROS, rosiglitazone; HOMA-IR, homeostasis model assessment of basal insulin resistance; IPGTT, intraperitoneal glucose tolerance test; HFD, high fat diet; SOCS-3, suppressor of cytokine signaling-3; TNF-α, tumour necrosis factor-α.