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Molecular genetics of pulmonary hypertension in children.

ABSTRACT: Until recently, the molecular aetiology of paediatric pulmonary hypertension (PH) was relatively poorly understood. While the TGF-β/BMP pathway was recognised as central to disease progression, genetic analyses in children were largely confined to targeted screening of risk genes in small cohorts, with clinical management extrapolated from adult data. In recent years, next-generation sequencing has highlighted notable differences in the genetic architecture underlying childhood-onset cases, with a higher genetic burden in children partly explained by comorbidities such as congenital heart disease. Here, we review recent genetic advances in paediatric PH and highlight important risk factors such as dysregulation of the transcription factors SOX17 and TBX4. Given the poorer prognosis in paediatric cases, molecular diagnosis offers a vital tool to enhance clinical care of children with PH.

SUBMITTER: Taha F

PROVIDER: S-EPMC9763127 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Molecular genetics of pulmonary hypertension in children.

Taha Fatima F Southgate Laura L

Current opinion in genetics & development 20220627

Until recently, the molecular aetiology of paediatric pulmonary hypertension (PH) was relatively poorly understood. While the TGF-β/BMP pathway was recognised as central to disease progression, genetic analyses in children were largely confined to targeted screening of risk genes in small cohorts, with clinical management extrapolated from adult data. In recent years, next-generation sequencing has highlighted notable differences in the genetic architecture underlying childhood-onset cases, with ...[more]

PMID: 35772304

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Project description:Idiopathic pulmonary fibrosis (IPF) is a severe progressive interstitial lung disease with a prevalence of 2 to 29 per 100,000 of the world's population. Aging is a significant risk factor for IPF, and the mechanisms of aging (telomere depletion, genomic instability, mitochondrial dysfunction, loss of proteostasis) are involved in the pathogenesis of IPF. The pathogenesis of IPF consists of TGF-β activation, epithelial-mesenchymal transition, and SIRT7 expression decrease. Genetic studies have shown a role of mutations and polymorphisms in mucin genes (MUC5B), in the genes responsible for the integrity of telomeres (TERC, TERC, TINF2, DKC1, RTEL1, PARN), in surfactant-related genes (SFTPC, SFTPCA, SFTPA2, ABCA3, SP-A2), immune system genes (IL1RN, TOLLIP), and haplotypes of HLA genes (DRB1*15:01, DQB1*06:02) in IPF pathogenesis. The investigation of the influence of reversible epigenetic factors on the development of the disease, which can be corrected by targeted therapy, shows promise. Among them, an association of a number of specific microRNAs and long noncoding RNAs was revealed with IPF. Therefore, dysregulation of transposons, which serve as key sources of noncoding RNA and affect mechanisms of aging, may serve as a driver for IPF development. This is due to the fact that pathological activation of transposons leads to violation of the regulation of genes, in the epigenetic control of which microRNA originating from these transposons are involved (due to the complementarity of nucleotide sequences). Analysis of the MDTE database (miRNAs derived from Transposable Elements) allowed the detection of 12 different miRNAs derived in evolution from transposons and associated with IPF (miR-31, miR-302, miR-326, miR-335, miR-340, miR-374, miR-487, miR-493, miR-495, miR-630, miR-708, miR-1343). We described the relationship of transposons with TGF-β, sirtuins and telomeres, dysfunction of which is involved in the pathogenesis of IPF. New data on IPF epigenetic mechanisms can become the basis for improving results of targeted therapy of the disease using noncoding RNAs.

Dataset Information

Molecular genetics of pulmonary hypertension in children.

Publications

Molecular genetics of pulmonary hypertension in children.

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