[Clinical and genetic analysis of a patient with short stature due to variant of RPL13 gene].

OBJECTIVE: To analyze the clinical phenotype and genetic characteristics of a patient with Isidor-Toutain spinal epiphyseal dysplasia (SEMD) due to variant of RPL13 gene. METHODS: A pregnant woman at 18 weeks of gestation who had presented at Quzhou Maternal and Child Health Care Hospital on January 14, 2023 was selected as the study subject. Whole exome sequencing (WES) was carried out for the patient, and candidate variant was validated by Sanger sequencing and bioinformatic analysis. RESULTS: The woman was 37 years old with extremely short stature (135 cm) and "O" shaped legs. WES revealed that she has harbored a c.548G>C (p.Arg183Pro) missense variant of the RPL13 gene (NM_000977.4). The same variant was not found in her fetus. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be likely pathogenic (PS4+PM2_Supporting+PP3+PP4). CONCLUSION: Isidor-Toutain type SEMD due to variants of the RPL13 gene may have variable expressivity and diverse clinical phenotypes. Above finding has facilitated the differential diagnosis and genetic counseling for this family.

Identification and structural analysis of a selective tropomyosin receptor kinase C (TRKC) inhibitor.

Tropomyosin receptor kinases (TRKs) are a family of TRKA, TRKB and TRKC isoforms. It has been widely reported that TRKs are implicated in a variety of tumors with several Pan-TRK inhibitors currently being used or evaluated in clinical treatment. However, off-target adverse events frequently occur in the clinical use of Pan-TRK inhibitors, which result in poor patient compliance, even drug discontinuation. Although a subtype-selectivity TRK inhibitor may avert the potential off-target adverse events and can act as a more powerful tool compound in the biochemical studies on TRKs, the high sequence similarities of TRKs hinder the development of subtype-selectivity TRK inhibitors. For example, no selective TRKC inhibitor has been reported. Herein, a selective TRKC inhibitor (L13) was disclosed, with potent TRKC inhibitory activity and 107.5-/34.9-fold selectivity over TRKA/B (IC50 TRKA/B/C = 1400 nM, 454 nM, 13 nM, respectively). Extensive molecular dynamics simulations illustrated that key interactions of L13 with the residues and diversely conserved water molecules in the ribose regions of different TRKs may be the structural basis of selectivity. This will provide inspiring insights into the development of subtype-selectivity TRK inhibitors. Moreover, L13 could serve as a tool compound to investigate the distinct biological functions of TRKC and a starting point for further research on drugs specifically targeting TRKC.

Association between single nucleotide polymorphisms of delta/notch-like epidermal growth factor (EGF)-related receptor (DNER) and Delta-like 1 Ligand (DLL 1) with the risk of type 2 diabetes mellitus in a Chinese Han population.

The aim of the study was to investigate the association between single nucleotide polymorphisms (SNPs), rs1861612 of delta/notch-like Epidermal Growth Factor (EGF)-related receptor (DNER) and rs1884190 in the Delta-like 1 ligand (DLL1) gene and type 2 diabetes mellitus (T2DM) susceptibility in a Chinese Han population. DNER rs1861612 and DLL1 rs1884190 polymorphisms were genotyped in patients with T2DM and age- and sex-matched T2DM-free controls from a Chinese Han population. A total of 298 patients with T2DM and 500 controls were enrolled in this study. We found that TC and TT genotypes of rs1861612 and variant T were associated with a significantly increased risk of T2DM. In contrast, the AG and AA genotypes of rs1884190 were not significantly associated with the risk of T2DM, even after further stratification analysis based on age or sex. Our results showed that DNER rs1861612 C to T change and variant T genotype may contribute to T2DM in a Chinese Han population.