Epigenetic Mechanisms in Neurofibromatosis Types 1 and 2

Abstract

Neurocutaneous syndromes, known as phakomatoses, encompass a diverse group of congenital conditions affecting the nervous system and skin, with neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2) among the most clinically significant. Both disorders are inherited in an autosomal dominant manner. NF1 presents with café-au-lait macules; cutaneous, subcutaneous, and plexiform neurofibromas; skeletal abnormalities; learning disabilities; and optic pathway gliomas, while NF2 is characterised by bilateral vestibular schwannomas, multiple meningiomas, ependymomas, and peripheral nerve schwannomas. Although germline mutations in the NF1 and NF2 tumour suppressor genes are well established, they do not fully explain the broad clinical variability observed, even among individuals carrying identical mutations. As increasingly recognised in other genetic diseases, epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodelling, and non-coding RNA (ncRNA) regulation, play a critical role in modulating gene expression and influencing disease severity. Despite important findings, the research remains fragmented, and a unified model is lacking. This review organises the current knowledge, emphasising how epigenetic alterations impact disease behaviour and outlining their potential as prognostic biomarkers and therapeutic targets. A deeper understanding of these mechanisms could lead to improved personalised management and the development of targeted epigenetic therapies for individuals with NF1 and NF2.

Keywords: DNA methylation; epigenetics; histone modifications; neurofibromatosis type 1; neurofibromatosis type 2; non-coding RNAs; phakomatoses.

Figure 1

Epigenetic regulation of pathogenesis and prognosis in neurofibromatosis type 1. (A) DNA methylation, (B) chromatin remodelling, (C) non-coding RNA. * Although NF1 promoter methylation has been implicated in pathogenesis of NF1, several studies have reported that such methylation events may not play a significant role in disease development. SAM: S-adenosylmethionine; MAP2K3: mitogen-activated protein kinase 3; MSH2: MutS homolog 2; NF1: neurofibromatosis type 1; RASSF1A: Ras association domain family member 1 isoform A; TALGN: transgelin; H3K27me3: trimethylation of lysine 27 on histone H3; KDM6: lysine demethylase 6; KDM4: lysine demethylase 4; TF: transcription factor; rs2151280: reference SNP ID 2151280; ANRIL: antisense non-coding RNA in the INK4 locus; MMP2: matrix metalloproteinase 2; p53: tumour suppressor p53; RAS: rat sarcoma virus oncogene; miR-29c: microRNA-29c; miR-34a: microRNA-34a; miR-10b: microRNA-10b; mRNA: messenger ribonucleic acid.