Aggregates of Mutant DNMT1 Are Linked to a Spectrum of Neurological Disorders (S34.007)

OBJECTIVE: To define the clinical spectrum of hereditary sensory neuropathy type 1E (HSAN1E), and investigate the functional significance of mutations in DNA maintenance methyltransferase (DNMT1). BACKGROUND: DNMT1 is the sole maintenance DNA methyltransferase in mammals. It is a major epigenetic regulator. Large cohort DNMT1 mutant studies have not been reported. Although genomic methylation is known abnormal the pathological mechanism is not understood. DESIGN/METHODS: We identified 9 HSAN1E kindreds (45 affected) and examined their phenotypes. We studied all mutants for cellular localization and protein degradation and the binding of DNMT1 mutants to the replication foci and heterochromatin. RESULTS: Five novel mutations within the targeting-sequence (TS) domain of DNMT1 were identified: p.C353F, p.T481P, p.P491L, p.Y524D, and p.I531N. Average survival age was 53.6 (sd=7.7, range:43-75ys), and average onset age 37.7 (sd=8.6, range:18-51ys). HSAN1E ultimately occurred with a triad of sensory axonal neuropathy, hearing loss and cognitive decline in all patients. Myoclonus, seizures, auditory hallucinations, sleep disorders and renal failure also occurred and often delayed the diagnosis. Hypersomnia, REM sleep disorder and/or narcolepsy were identified in 11 of 45 persons. Global brain atrophy was found in 12 of 14 undergoing brain MRI. Five of 6 patients who underwent EEGs showed low amplitude (delta) frontal-predominant abnormality. Marked variability in cognitive deficits was observed, but the majority of patients (89[percnt]) developed significant cognitive deficit by the age 45yrs. Cognitive function decline often started with personality changes and psychiatric manifestations. All DNMT1 mutant proteins misfold reduced enzyme activity, form cytoplasmic aggresomes and lose their binding ability to heterochromatin, translocating to the cytoplasm during G2 cell cycle. CONCLUSIONS: Mutations of DNMT1 cause a diverse spectrum of central and peripheral nervous system presentations. Mutations lead to protein homeostasis imbalance and the formation of aggresomes. Aggresome-induced autophagy is implicated in the pathogenesis in combination with aberrant genome methylation pattern. Disclosure: Dr. Baets has nothing to disclose. Dr. Duan has nothing to disclose. Dr. Wu has nothing to disclose. Dr. Smith has nothing to disclose. Dr. Seeley has nothing to disclose. Dr. Mademan has nothing to disclose. Dr. McGrath has nothing to disclose. Dr. Beadell has nothing to disclose. Dr. Khoury has nothing to disclose. Dr. Botuyan has nothing to disclose. Dr. Mer has nothing to disclose. Dr. Worrell has nothing to disclose. Dr. Hojo has nothing to disclose. Dr. Delone has nothing to disclose. Dr. Laura has nothing to disclose. Dr. Liu has nothing to disclose. Dr. Senderek has nothing to disclose. Dr. Weis has nothing to disclose. Dr. Van den Bergh has nothing to disclose. Dr. Merrill has nothing to disclose. Dr. Reilly has nothing to disclose. Dr. Houlden has nothing to disclose. Dr. Grossman has nothing to disclose. Dr. Scherer has received personal compensation for activities with Simon-Kucher & Partners LLC. Dr. De Jonghe has nothing to disclose. Dr. Dyck has nothing to disclose. Dr. Klein has nothing to disclose.