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De Novo STXBP1 Mutations in Mental Retardation and Nonsyndromic

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De Novo STXBP1 Mutations in Mental Retardation and Nonsyndromic 14. Post MJ, Yiannoutsos C, Simpson D, et al. Progressive multi- focal leukoencephalopathy in AIDS: are there any MR findings De Novo STXBP1 Mutations useful to patient management and predictive of patient survival? AIDS Clinical Trials Group, 243 Team. AJNR Am J Neurora- in Mental Retardation and diol 1999;20:1896–1906. 15. Shintaku M, Matsumoto R, Sawa H, Nagashima K. Infection Nonsyndromic Epilepsy with JC virus and possible dysplastic ganglion-like transforma- 1 2 tion of the cerebral cortical neurons in a case of progressive Fadi F. Hamdan, PhD, Ame´lie Piton, PhD, Julie Gauthier, PhD,2 Anne Lortie, MD,1 multifocal leukoencephalopathy. J Neuropathol Exp Neurol 3 2 2000;59:921–929. Franc¸ois Dubeau, MD, Sylvia Dobrzeniecka, MSc, Dan Spiegelman, MSc,2 Anne Noreau, MSc,2 16. Del Valle L, Delbue S, Gordon J, et al. Expression of JC virus 1 2 T-antigen in a patient with MS and glioblastoma multiforme. Ste´phanie Pellerin, RN, Me´lanie Coˆte´, BSc, Edouard Henrion, MSc,2 E´ric Fombonne, MD,4 Neurology 2002;58:895–900. 5 17. Raj GV, Khalili K. Transcriptional regulation: lessons from the hu- Laurent Mottron, MD, PhD, Claude Marineau, MSc, MBA,2 Pierre Drapeau, PhD,6 man neurotropic polyomavirus, JCV. Virology 1995;213:283–291. 2 7 18. Messam CA, Hou J, Gronostajski RM, Major EO. Lineage Ronald G. Lafrenie`re, PhD, Jean Claude Lacaille, PhD, Guy A. Rouleau, MD, PhD,2 and pathway of human brain progenitor cells identified by JC virus 1 susceptibility. Ann Neurol 2003;53:636–646. Jacques L. Michaud, MD 19. Lima MA, Drislane FW, Koralnik IJ. Seizures and their out- come in progressive multifocal leukoencephalopathy. Neurology 2006;66:262–264. We sequenced genes coding for components of the SNARE complex (STX1A, VAMP2, SNAP25) and their regulatory proteins (STXBP1/Munc18-1, SYT1), which are essential for neurotransmission, in 95 patients with idiopathic mental re- tardation. We identified de novo mutations in STXBP1 (nonsense, p.R388X; splicing, c.169ϩ1GϾA) in two pa- tients with severe mental retardation and nonsyndromic ep- ilepsy. Reverse transcriptase polymerase chain reaction and sequencing showed that the splicing mutation creates a stop codon downstream of exon-3. No de novo or deleterious mutations in STXBP1 were found in 190 control subjects, or in 142 autistic patients. These results suggest that STXBP1 disruption is associated with autosomal dominant mental re- tardation and nonsyndromic epilepsy. Ann Neurol 2009;65:748–753 From the 1Centre of Excellence in Neuromics of Universite´de Montre´al and Synapse to Disease Group, Centre Hospitalier Uni- versitaire Sainte-Justine Research Center; 2Centre Hospitalier de L’Universite´ de Montre´al Research Center and Department of Med- icine, Universite´ de Montre´al; 3Department of Neurology and Neu- rosurgery, Montreal Neurological Institute, McGill University; 4De- partment of Psychiatry, Montreal Children’s Hospital, McGill University, Montreal; 5Centre de Recherche Fernand-Se´guin, Hoˆpi- tal Rivie`re-des-Prairies, Universite´ de Montre´al; and Departments of 6Pathology and Cell Biology and 7Physiology, Le Groupe de Re- cherche sur le Syste`me Nerveux Central and Le Groupe Fonds de la Recherche en Sante´ du Quebec de Recherche sur le Syste`me Nerveux Central, Universite´ de Montre´al, Montreal, Quebec, Can- ada. Address correspondence to Dr Michaud, Research Center, CHU Sainte-Justine, 3175 Coˆte Sainte-Catherine, Montreal, Que- bec, Canada H3T 1C5. E-mail: jacques.michaud@recherche-ste- justine.qc Potential conflict of interest: Nothing to report. Additional Supporting Information may be found in the online ver- sion of this article. Received Sep 26, 2008, and in revised form Nov 10. Accepted for publication Dec 5, 2008. Published in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ana.21625 748 © 2009 American Neurological Association Mental retardation (MR), the most frequent severe Blood samples were collected from all members of these co- handicap of children, is defined by the presence of sig- horts, as well as from their parents after approval by institu- nificant limitations in cognitive and adaptive behav- tional ethics committees. Genomic DNA was extracted from ior.1 Most MR genes identified so far are either located blood samples using the Puregene DNA kit (Quigan, Mis- on the X chromosome or are associated with an auto- sissauga, ON, Canada). Paternity and maternity of each in- somal recessive mode of inheritance. Only a small dividual of all families were confirmed using six informative unlinked microsatellite markers (D2S1327, D3S1043, number of autosomal dominant MR genes are known, D4S3351, D6S1043, D8S1179, D10S677). Polymerase in part, because MR results in lower reproductive fit- chain reaction (PCR) amplification of the exons and intronic ness, decreasing the likelihood of identifying families splice junctions of STX1A, VAMP2, SNAP25, STXBP1 (iso- that are amenable to linkage analysis. The fact that de forms a,b), and SYT1, and subsequent sequencing and mu- novo copy number variants represent the most com- tation analyses were conducted according to standard proce- monly recognized cause of MR indicates that monoal- dures (see supplementary materials). lelic lesions are sufficient to cause MR and raises the possibility that smaller de novo genetic lesions, such as RNA Analysis point mutations, also represent a major cause of MR. Total cellular RNA from Patient 1 and her mother was iso- The identification of de novo point mutations, how- lated from blood using the TRIzol reagent, and reverse- ever, must rely on the sequencing of candidate genes. transcribed (3␮g) using MMLV reverse transcriptase (In- Defects in synaptic function are thought to underlie vitrogen, La Jolla, CA). Complementary DNA (cDNA) was many common neurodevelopmental brain disorders, PCR-amplified with STXBP1-specific primers flanking including autism and MR.1,2 One of the key events of intron-3 (contains the splicing mutation): STXBP1_ex2F: interneuronal communication at the synapse is the re- 5ЈAAGAAGAAGGGGGAATGGAA-3Ј and STXBP1_ex4- 2ϩ 5R: 5Ј-GAGAGTGGACGGACTTCTCG-3Ј, and with GA- lease of neurotransmitters by Ca -triggered synaptic Ј vesicle exocytosis. This vesicular fusion event is mainly PDH-specific primers GAPDH_F: 5 -CCA CTCCTCCA- CCTTTGAC-3Ј and GAPDH_R: 5Ј-ACCCTGTTGCTG- mediated by a well-characterized group of SNARE pro- TAGCCA-3Ј. The intensity of each PCR band was calcu- teins comprising the synaptic vesicle protein synapto- lated using Quantity One software vs4.6.1 (BioRad, Missis- brevin-2/VAMP2, and plasma membrane proteins syn- sauga, ON, Canada). Statistical analysis (n ϭ 4) was con- taxin-1A/STX1A and SNAP25, which altogether bring ducted using a Student’s t test. cDNA from Patient 1 and and fuse synaptic vesicles at the presynaptic plasma mem- her mother were also amplified using forward primer brane, releasing their neurotransmitter content into the STXBP1_ex3-mut-int3F:5Ј-AGGGCATAACGAatgagca-3Ј, synaptic cleft.3,4 This process is regulated by Munc18-1/ specific for the mutated allele (c.169ϩ1GϾA splicing muta- STXBP1, which is essential for SNARE complex forma- tion; underlined), and reverse primer STXBP1_ex4-5R. Re- tion and synaptic vesicle fusion, and by synaptotagmin-1/ sulting PCR products were subcloned into TOPO-TA ϩ SYT1, the main Ca2 sensor in neurons that mediates PCR2.1 (Invitrogen) and sequenced. ϩ fast synaptic vesicle fusion after Ca2 influx.3,5–8 We postulated that de novo mutations in autosomal Results genes that are involved in neurotransmission could lead We identified three heterozygous mutations in to cognitive deficits in humans. Specifically, we se- STXBP1 in three patients of our MR cohort. These quenced the coding exons and their flanking intronic mutations, including a missense (c.455CϾG; regions of genes encoding the main components of the p.S152C), a nonsense (c.1162CϾT; p.R388X), and a synaptic SNARE machinery (STX1A, VAMP2, mutation located in the consensus splice donor site of SNAP25), together with those of their regulatory pro- intron 3 (c.169ϩ1GϾA), were found in single pa- teins (STXBP1 and SYT1), in 95 patients with idio- tients. The missense c.455CϾG is unlikely to be pathic MR. We report the identification of de novo pathogenic because it is transmitted from a healthy fa- truncating and splicing mutations in STXBP1 in two ther. In contrast, the splice junction c.169ϩ1GϾA patients with MR and nonsyndromic epilepsy. (Patient 1) and the nonsense c.1162CϾT (Patient 2) mutations were de novo (not present in blood DNA of Subjects and Methods the parents of the affected individuals) (Fig 1). Se- quencing all STXBP1 exons and intronic junctions in Subjects and DNA Screening two control cohorts by our group (n ϭ 190) and by Ninety-five French Canadian sporadic cases of idiopathic the Sanger Institute’s ExoSeq project (n ϭ 48 Europe- MR without growth abnormalities or specific dysmorphic ans; http://www.sanger.ac.uk/cgi-bin/humgen/exoseq/ features were recruited for this study. A subset of the MR ϭ patients (25/95) also displayed some forms of epilepsy. exoseqview?gene STXBP1) did not show any splicing Moreover, cohorts of 142 patients with autism spectrum dis- or amino acid–altering mutations. No amino acid–al- order (ASD) and 190 healthy ethnically matched individuals tering or splicing mutations were found in the other were studied. Additional details concerning the MR and four sequenced genes (STX1A, VAMP2, SNAP25, ASD cohorts are provided in the supplementary materials. SYT1) in the MR cohort. Hamdan et al: STXBP1 and Mental Retardation 749 primer (ex3-mut-int3F) targeting the exon-3/intron-3 junction and containing the c.169ϩ1GϾA mutation at its 3Ј-end, as well as a reverse primer targeting the Fig 1. Location of the heterozygous de novo mutations of STXBP1. (A) Schematic presentation of STXBP1 exon-intron regions (isoform a: NM_003165; isoform b, which lacks exon 19: NM_001032221); filled boxes represent coding exons, whereas white boxes indicate untranslated sequence. (B) Do- main organization of STXBP1 based on the rat STXBP1 crys- tal structure.9 Amino acids 28 to 582 represent SEC1 do- Fig 2.
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