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Weaver Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Weaver syndrome is a rare congenital pediatric disorder characterized by skeletal overgrowth (e.g., tall stature), distinctive craniofacial and digital abnormalities (e.g., camptodactyly of the fingers and/or toes), advanced bone age, variable intellectual disability (ranging from normal intellect to severe intellectual disability), other clinical features (e.g., poor coordination, soft doughy skin, umbilical hernia, abnormal tone, and hoarse low cry in infancy), and increased risk for neuroblastoma. Mutations in the enhancer of zeste homolog 2 gene (EZH2) on chromosome 7q36.1 encoding a histone methyltransferase appear to be responsible for Weaver syndrome [1,2].
Epigenetic Regulatory Enzymes: mutation Prevalence and Coexistence in Cancers
Published in Cancer Investigation, 2021
Amit Sharma, Hongde Liu, Martina C. Herwig-Carl, Tikam Chand Dakal, Ingo G H Schmidt-Wolf
Histone methylation, on the other hand, occurs mainly at lysine (K) or arginine (R) residues on histone tails and is associated with either transcriptional activation or repression, established by histone methyltransferases (HMTs) or removed by histone demethylases (HDMs). Enhancer of zeste homolog 2 (EZH2), one of the best-studied HMT enzymes specifically targeting H3K27 residues, has been found to be upregulated in several cancers (89,90). In addition, overexpression EZH2 in uveal melanoma is associated with an adverse clinical outcome (91) One study identified high incidence of EZH2 mutations (Y646, A682, and A692) in 27% cases of follicular lymphoma cases (92). Similarly, the mutation A687V in EZH2 has been suggested as a driver mutation in Non-Hodgkin lymphomas (93). The mutations in EZH2 gene were also linked to Weaver syndrome and Ataxia telangiectasia (94,95). Among histone demethylase, studies have also highlighted the role of LSD1 (Lysine demethylase 1) in cancer stemness (96,97). Similarly, UTX was first reported as a highly mutated histone H3K27 demethylase in a survey of different human cancers/cancer cell lines including acute myeloid leukemia, breast cancer, colorectal adenocarcinoma, endometrial adenocarcinoma, bladder carcinoma, chronic myeloid leukemia, and glioblastoma (98). To mention, UTY (a homologous gene of UTX) is rarely mutated in human cancers, but a recent study reported few mutations that occur in cutaneous melanoma, urothelial carcinoma of the bladder, B-cell lymphoma, small cell lung cancer, oligodendroglioma, and chondroblastic osteosarcoma (99). In compare to histone lysine methyltransferases (KMTs), the other counterpart of histone methyltransferases (HMTs), i.e. protein arginine methyltransferases (PRMTs) has also been linked to many cancers (100). Specifically, PRMT5 overexpression in cancers of different types and aggressiveness including B and T cell lymphoma, metastatic melanoma, neuroblastoma and glioblastoma, germ cell tumors, ovarian cancer, nasopharyngeal cancer, breast cancer, colorectal cancer, and gastric cancer has been discussed (101). Recently, it was shown that PRMT5 repressed transcription of tumor suppressor IRX1 via recruitment of DNMT3A on promoter in gastric cancer (102).