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  Mutation screening of ASMT, the last enzyme of the melatonin pathway, in a large sample of patients with intellectual disability

Pagan, C., Botros, H. G., Poirier, K., Dumaine, A., Jamain, S., Moreno, S., et al. (2011). Mutation screening of ASMT, the last enzyme of the melatonin pathway, in a large sample of patients with intellectual disability. BMC Med Genet, 12, 17. Retrieved from http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21251267 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3034665/pdf/1471-2350-12-17.pdf?tool=pmcentrez.

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Pagan, C., Author
Botros, H. G., Author
Poirier, K., Author
Dumaine, A., Author
Jamain, S., Author
Moreno, S., Author
de Brouwer, A., Author
Van Esch, H., Author
Delorme, R., Author
Launay, J. M., Author
Tzschach, A.1, Author              
Kalscheuer, V.2, Author              
Lacombe, D., Author
Briault, S., Author
Laumonnier, F., Author
Raynaud, M., Author
van Bon, B. W., Author
Willemsen, M. H., Author
Leboyer, M., Author
Chelly, J., Author
Bourgeron, T., Author more..
Affiliations:
1Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433549              
2Chromosome Rearrangements and Disease (Vera Kalscheuer), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479642              

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Free keywords: Acetylserotonin O-Methyltransferase/*genetics; Case-Control Studies; Genetic Testing; Humans; Intellectual Disability/complications/epidemiology/*genetics; Melatonin/biosynthesis; Metabolic Networks and Pathways; Mutation; Sequence Analysis, DNA; Sleep Disorders/etiology/genetics
 Abstract: BACKGROUND: Intellectual disability (ID) is frequently associated with sleep disorders. Treatment with melatonin demonstrated efficacy, suggesting that, at least in a subgroup of patients, the endogenous melatonin level may not be sufficient to adequately set the sleep-wake cycles. Mutations in ASMT gene, coding the last enzyme of the melatonin pathway have been reported as a risk factor for autism spectrum disorders (ASD), which are often comorbid with ID. Thus the aim of the study was to ascertain the genetic variability of ASMT in a large cohort of patients with ID and controls. METHODS: Here, we sequenced all exons of ASMT in a sample of 361 patients with ID and 440 controls. We then measured the ASMT activity in B lymphoblastoid cell lines (BLCL) of patients with ID carrying an ASMT variant and compared it to controls. RESULTS: We could identify eleven variations modifying the protein sequence of ASMT (ID only: N13H, N17K, V171M, E288D; controls only: E61Q, D210G, K219R, P243L, C273S, R291Q; ID and controls: L298F) and two deleterious splice site mutations (IVS5+2T>C and IVS7+1G>T) only observed in patients with ID. We then ascertained ASMT activity in B lymphoblastoid cell lines from patients carrying the mutations and showed significantly lower enzyme activity in patients carrying mutations compared to controls (p = 0.004). CONCLUSIONS: We could identify patients with deleterious ASMT mutations as well as decreased ASMT activity. However, this study does not support ASMT as a causative gene for ID since we observed no significant enrichment in the frequency of ASMT variants in ID compared to controls. Nevertheless, given the impact of sleep difficulties in patients with ID, melatonin supplementation might be of great benefit for a subgroup of patients with low melatonin synthesis.

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 Dates: 2011
 Publication Status: Published in print
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Title: BMC Med Genet
Source Genre: Journal
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Pages: - Volume / Issue: 12 Sequence Number: - Start / End Page: 17 Identifier: ISSN: 1471-2350 (Electronic) 1471-2350 (Linking)