Dominant NARS1 mutations causing axonal Charcot-Marie-Tooth disease expand NARS1-associated diseases.

Pathogenic variants in six aminoacyl-tRNA synthetase (ARS) genes are implicated in neurological disorders, most notably inherited peripheral neuropathies. ARSs are enzymes that charge tRNA molecules with cognate amino acids. Pathogenic variants in asparaginyl-tRNA synthetase (NARS1) cause a neurological phenotype combining developmental delay, ataxia and demyelinating peripheral neuropathy. NARS1 has not yet been linked to axonal Charcot-Marie-Tooth disease. Exome sequencing of patients with inherited peripheral neuropathies revealed three previously unreported heterozygous NARS1 variants in three families. Clinical and electrophysiological details were assessed. We further characterized all three variants in a yeast complementation model and used a knock-in mouse model to study variant p.Ser461Phe. All three variants (p.Met236del, p.Cys342Tyr and p.Ser461Phe) co-segregate with the sensorimotor axonal neuropathy phenotype. Yeast complementation assays show that none of the three NARS1 variants support wild-type yeast growth when tested in isolation (i.e. in the absence of a wild-type copy of NARS1), consistent with a loss-of-function effect. Similarly, the homozygous knock-in mouse model (p.Ser461Phe/Ser472Phe in mouse) also demonstrated loss-of-function characteristics. We present three previously unreported NARS1 variants segregating with a sensorimotor neuropathy phenotype in three families. Functional studies in yeast and mouse support variant pathogenicity. Thus, NARS1 is the seventh ARS implicated in dominant axonal Charcot-Marie-Tooth disease, further stressing that all dimeric ARSs should be evaluated for Charcot-Marie-Tooth disease.

Vessel remodelling, pregnancy hormones and extravillous trophoblast function.

During early human pregnancy, extravillous trophoblast (EVT) cells from the placenta invade the uterine decidual spiral arterioles and mediate the remodelling of these vessels such that a low pressure, high blood flow can be supplied to the placenta. This is essential to facilitate normal growth and development of the foetus. Defects in remodelling can manifest as the serious pregnancy complication pre-eclampsia. During the period of vessel remodelling three key pregnancy-associated hormones, human chorionic gonadotrophin (hCG), progesterone (P(4)) and oestradiol (E(2)), are found in high concentrations at the maternal-foetal interface. Potentially these hormones may control EVT movement and thus act as regulators of vessel remodelling. This review will discuss what is known about how these hormones affect EVT proliferation, migration and invasion during vascular remodelling and the potential relationship between hCG, P(4), E(2) and the development of pre-eclampsia.

The effects of human chorionic gonadotrophin, progesterone and oestradiol on trophoblast function.

Remodelling of the uterine vasculature during the first trimester of human pregnancy requires invasion of trophoblast from the placenta into decidual spiral arterioles. The pregnancy-associated hormones human chorionic gonadotropin (hCG), progesterone (P(4)) and oestradiol (E(2)) are present at high concentrations at the maternal-fetal interface during the remodelling period and thus may contribute to the regulation of trophoblast movement. This study examined the effects of these hormones on trophoblast functions. HTR8/SVneo cells were treated with hCG (5-100mIU/mL), P(4) (20nM-20µM) or E(2) (0.07-734nM). hCG significantly stimulated migration and MMP-9 activity but did not affect cell numbers. P(4) significantly inhibited migration, MMP-2 and -9 activity and reduced cell numbers. E(2) had no effect on migration, MMP activity or cell numbers. We conclude that hCG and P(4), but not E(2), play direct roles in controlling trophoblast invasion, acting as positive and negative stimuli respectively to regulate trophoblast movement during vascular remodelling in early pregnancy.