Mutation screening of ASMT, the last enzyme of the melatonin pathway, in a large sample of patients with Intellectual Disability
1 Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France
2 CNRS URA 2182 "Genes, synapses et cognition", Institut Pasteur, Paris, France
3 University Paris Descartes, Paris, France
4 Institut Cochin, CNRS ULD 8104, Paris, France
5 Inserm U 955, IMRB, Psychiatry Genetics, Creteil, F-94000, France
6 Foundation Fondamental, Creteil, France
7 Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
8 Center for Human Genetics, University Hospitals Leuven, B-3000 Leuven, Belgium
9 Service de Biochimie, INSERM U942, Hopital Lariboisière, Assistance Publique-Hopitaux de Paris, Paris, France
10 Max Planck Institute for Molecular Genetics, Department Ropers, Berlin, Germany
11 Service de Génétique Médicale, Hôpital Pellegrin, CHU de Bordeaux, Bordeaux, France
12 UMR 6218, CNRS, IEM, équipe « génétique expérimentale et moléculaire », université d'Orléans, Orléans, France
13 Centre hospitalier régional d'Orléans, Orléans, France
14 Inserm U930 "Imaging and Brain", Tours, France
15 University François-Rabelais, Tours, France
16 CNRS ERL3106, Tours France
17 Centre Hospitalier Régional Universitaire, Service de Génétique, Tours, France
18 University Paris-East, Faculty of Medicine, UMR-S 955, Creteil, F-94000, France
19 AP-HP, Henri Mondor-Albert Chenevier Group, Department of Psychiatry, Creteil, F-94000, France
20 University Denis Diderot Paris 7, Paris, France
BMC Medical Genetics 2011, 12:17 doi:10.1186/1471-2350-12-17Published: 20 January 2011
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.
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.
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).
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.