A novel structural variant of RET causes familial Hirschsprung's disease via nonsense-mediated mRNA decay

Hirschsprung's disease(HsCR)is the most common type of developmental gastrointestinal malformation causing intestinal obstruction in children,with an incidence of 1/5000 in live births.1 it is characterized by the absence of intrinsic ganglion cells in the myenteric and submucosal plexuses of the distal gastrointestinal tract,leading to the dysregulation of smooth muscle contraction/relaxation and resulting in intestinal obstruction.Depending on the length of the aganglionic intestine,HSCR can be categorized into short-segmental HSCR(S-HSCR),which affects up to the sigmoid colon from the anus,and long-segmental HSCR(LHSCR),which affects beyond the sigmoid colon.1 In some rare conditions,aganglionic lesions can affect the full length of the colon or even the whole intestine.

miR-181b-5p/SOCS2/JAK2/STAT5 axis facilitates the metastasis of hepatoblastoma

Introduction:Hepatoblastoma(HB)is a malignant liver tumor predominantly found in children and tumor metastasis is one of the main causes of poor prognosis in affected patients.The precise molecular mechanisms responsible for HB metastasis remain incom-pletely understood.However,there is evidence suggesting a connection between the dysregulation of microRNAs(miRNAs)and the progression of tumor metastasis in HB.Methods:The study utilized weighted gene co-expression network analysis(WGCNA)to analyze a miRNA microarray dataset of HB.The expression of miR-181b-5p in HB tissues and cells was detected using quantitative real-time PCR.The impact of miR-181b-5p on the metastatic capacity of HB was evaluated through scratch and Transwell assays.The effects of exogenously expressing miR-181b on the metastatic phenotypes of HB cells were evaluated in vivo.Furthermore,a luciferase reporter assay was performed to validate a potential target of miR-181b-5p in HB.Results:We found that miR-181b-5p was highly expressed in HB tissues and HB cell lines.Overexpression of miR-181b enhanced scratch healing,cell migration,and invasion abilities in vitro,as well as enhancing HB lung metastasis potential in vivo.Dual-luciferase reporter assays showed that Suppressor Of Cytokine Signaling 2(SOCS2)was a direct target of miR-181b.The overexpression of miR-181b resulted in the suppression of SOCS2 expression,subsequently activating the epithelial-mesenchymal transition and JAK2/STAT5 signaling pathways.The rescue experiment showed that SOCS2 overexpression attenuated the effects of miR-181b on HB cells.Conclusion:Our study showed that miR-181b promotes HB metastasis by targeting SOCS2 and may be a potential therapeutic target for HB.

Weakened tanning ability is an important mechanism for evolutionary skin lightening in East Asians

The evolution of light-skin pigmentation among Eurasians is considered as an adaptation to the high-latitude environments.East Asians are ideal populations for studying skin color evolution because of the complex environment of East Asia.Here,we report a strong selection signal for the pigmentation gene phenylalanine hydroxylase(PAH)in light-skinned Han Chinese individuals.The intron mutation rs10778203 in PAH is enriched in East Asians and is significantly associated with skin color of the back of the hand in Han Chinese males(P<0.05).In vitro luciferase and transcription factor binding assays show that the ancestral allele of rs10778203 could bind to SMAD2 and has a significant enhancer activity for PAH.However,the derived T allele(the major allele in East Asians)of rs10778203 decreases the binding activity of transcription factors and enhancer activity.Meanwhile,the derived T allele of rs10778203 shows a weaker ultraviolet radiation response in A375 cells and zebrafish embryos.Furthermore,rs10778203 decreases melanin production in transgenic zebrafish embryos after ultraviolet B(UVB)treatment.Collectively,PAH is a potential pigmentation gene that regulates skin tanning ability.Natural selection has enriched the adaptive allele,resulting in weakened tanning ability in East Asians,suggesting a unique genetic mechanism for evolutionary skin lightening in East Asians.