Mutation screening of ASMT, the last enzyme of the melatonin pathway, in a large sample of patients with intellectual disability.
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.
Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France.
Cecile
C
Pagan
Hany Goubran
HG
Botros
Karine
K
Poirier
Anne
A
Dumaine
Stéphane
S
Jamain
Sarah
S
Moreno
Arjan
A
de Brouwer
Hilde
H
Van Esch
Richard
R
Delorme
Jean-Marie
JM
Launay
Andreas
A
Tzschach
Vera
V
Kalscheuer
Didier
D
Lacombe
Sylvain
S
Briault
Frédéric
F
Laumonnier
Martine
M
Raynaud
Bregje W
BW
van Bon
Marjolein H
MH
Willemsen
Marion
M
Leboyer
Jamel
J
Chelly
Thomas
T
Bourgeron
D000121:Acetylserotonin O-Methyltransferase / Q000235:genetics*; D016022:Case-Control Studies; D005820:Genetic Testing; D006801:Humans; D008607:Intellectual Disability / Q000150:complications / Q000453:epidemiology / Q000235:genetics*; D008550:Melatonin / Q000096:biosynthesis; D053858:Metabolic Networks and Pathways; D009154:Mutation; D017422:Sequence Analysis, DNA; D012893:Sleep Wake Disorders / Q000209:etiology / Q000235:genetics
D000121:Acetylserotonin O-Methyltransferase; D008550:Melatonin
Science. 2007 Nov 16;318(5853):1144-6
18006748
Eur J Hum Genet. 2006 Jun;14(6):701-13
16721406
PLoS One. 2010 Jul 15;5(7):e11495
20657642
J Ment Defic Res. 1991 Aug;35 ( Pt 4):269-90
1757978
J Neuroendocrinol. 2003 Apr;15(4):427-31
12622845
J Pineal Res. 2010 May;48(4):311-7
20433639
PLoS One. 2008 Aug 26;3(8):e3055
18725972
Pharmacol Rev. 2003 Jun;55(2):325-95
12773631
Sleep Med Rev. 2005 Feb;9(1):11-24
15649735
Mol Psychiatry. 2007 Nov;12(11):977-9
17957233
Nat Neurosci. 1999 May;2(5):401-3
10321240
Nat Genet. 2009 Jan;41(1):82-8
19060908
PLoS Genet. 2008 May 30;4(5):e1000040
18516223
Cold Spring Harb Symp Quant Biol. 2007;72:645-54
18419324
Biol Psychiatry. 2005 Jan 15;57(2):134-8
15652871
Neuro Endocrinol Lett. 2000;21(1):31-34
11455326
J Autism Dev Disord. 1995 Dec;25(6):641-54
8720032
Dev Med Child Neurol. 2009 May;51(5):340-9
19379289
Mol Psychiatry. 2008 Jan;13(1):90-8
17505466
BMC Med Genomics. 2010 Apr 08;3:10
20377855
Psychoneuroendocrinology. 2009 Jun;34(5):752-61
19167832
Res Dev Disabil. 2001 Jul-Aug;22(4):255-72
11523951
N Engl J Med. 1997 Jan 16;336(3):186-95
8988899
J Neurosci Res. 2003 May 15;72(4):454-60
12704807
Nat Genet. 2009 Jan;41(1):89-94
19060909