| Author: | Yeung, Hoi Sang |
| Title: | ATM mutant variants and their differential effects on myelin and cerebrovascular pathology in ataxia telangiectasia – genomic diagnosis for rare but catastrophic disease |
| Advisors: | Tse, Kai-hei Franki (HTI) |
| Degree: | Ph.D. |
| Year: | 2026 |
| Department: | Department of Health Technology and Informatics |
| Pages: | 318 pages : color illustrations |
| Language: | English |
| Abstract: | Ataxia Telangiectasia (A-T) Mutated protein (ATM) is a major kinase that responds to DNA double strand breaks. A spectrum of pathogenic mutations of ATM is known to cause this rare genetic disease with cerebellar symptoms of different severity. Myelin pathology emerges as one of the neurological deficits in young A-T patients, but the mechanism is unknown. We aim to delineate the divergent effects of different ATM mutations on oligodendrocyte (OL) lineage. The postmortem brain tissue of A-T patients were employed for histological and transcriptomic study, showing distinct pathology in A-T cerebellum and cerebral cortex. Divergent severity of A-T pathology was found among A-T patients, showing differential effect of pathogenic mutations in ATM gene. The translational study was followed with a histological investigation where OL pathology was validated through Atm deficient mice model, AtmBal (B6;129S4-Atmtm1Bal/J), where the Atm exons was disrupted with no residual ATM activity, and AtmAwb (B6.129S6-Atmtm1Awb/J), where partial Atm mutation is being validated in a model harbouring truncated but active Atm residue. Atm deficient mice showed a significant decline of CC1 positive cell, marker of mature OLs, in both frontal and motor cortex region at 4 month-old. Region-specific effect of Atm deficiency on mature OL was consistant with the slight decline in cognitive performance of aging ATM deficient mice in behavioural test. The essential role of ATM in OL maturation was further confirmed with murine glial primary culture with intrinsic Atm mutation. In silico prediction of ATM-MBP interaction was verified with immunoprecipitation experiment, demonstrating potential mechanism of ATM affecting the maturation process of OL. This study provided detailed investigation on A-T myelin pathology and subsequence mechanism, which also raise the potential correlation between cognitive performance and myelin pathology. Moreover, the advantage of targeted long read sequencing on rare disease diagnosis was emphasized in this study, especially Nanopore targeted sequencing. Improved efficiency and convenience of detecting mutations in desired regions could be achieved with Nanopore sequencing. Adaptive sampling could be the further approach of targeting desire regions with Nanopore sequencing. |
| Rights: | All rights reserved |
| Access: | open access |
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