Histone lysine methylation and related genes in developmental disorders

Abstract

Histone lysine methylation (HKM) and demethylation are important epigenetic changes that have been implicated in health and disease. Therefore, it is relevant to study the impact of Histone Lysine Methyltransferases (KMTs) and Histone Lysine Demethylases (KDMs) in human development and the effects of disrupting variants in their encoding genes on developmental disorders (DD), using Kabuki syndrome (KS) as a HKM disorder model. Overall, variants in genes that encode for KMTs and KDMs genes explain >1.5% of patients with DD. These variants are mostly de novo, have a dominant inheritance, and the haploinsufficiency is the main mechanism of disease. In this project, three novel dominant disorders were associated to heterozygous, loss-of-function variants in KMT2C, ASH1L and KMT5B , whereas bi-allelic variants in KDM5B caused a novel recessive DD. Although missense variants (MVs) are difficult to interpret, the comparison of control variants versus those detected in cancers or DDs in terms of protein location may help to clarify their clinical significance. This analysis identified significant clustering of Cancer- MVs and KS-MVs in the PHD#3 and #4, RING#4 and SET domains. Cancer-MVs and KSMVs tended to affect more conserved residues, KS-MVs were more likely to increase the energy for protein folding, and Cancer-MVs are more likely to disrupt protein interactions. Kabuki syndrome type 2 (KS2) had not been completely characterised. It was demonstrated that many of the manifestations of KS2 are indistinguishable from those reported for KS or KS1, albeit a less typical facies and a higher frequency of hypoglycaemia may help to differentiate KS2 from KS1. Also, as a X-linked dominant disorder, males with KS2 have more severe phenotype. Similarly, individuals with PTVs have a more severe phenotype as well. Patients with KS-like phenotype negative for KMT2D and KDM6A may have variants in other genes. In this project, 5 individuals with de novo heterozygous EIF5A1 variants and overlapping features including intellectual disability, microcephaly and micrognathia were identified, some of them resembling KS. Functional analyses in yeast and zebrafish demonstrated impaired eIF5A function and recapitulation of human phenotype. Remarkably the mutation defects were partially rescued by spermidine.

Date of Award	31 Dec 2019
Original language	English
Awarding Institution	The University of Manchester
Supervisor	William Newman (Supervisor) & Siddharth Banka (Supervisor)