De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsy

Abstract

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 retardation. We identified de novo mutations in STXBP1 (nonsense, p.R388X; splicing, c.169+1G>A) in two patients with severe mental retardation and nonsyndromic epilepsy. 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 retardation and nonsyndromic epilepsy.

Intellectual disability without epilepsy associated with STXBP1 disruption

“…We selected sporadic cases to increase the likelihood of finding de novo mutation. In the context of this study, and of our previous one, 7 NSID was defined using the following criteria: (1) diagnosis of ID established on a clinical basis using standardized developmental or IQ tests; (2) absence of specific dysmorphic features, as assessed by an experienced clinical geneticist; (3) birth weight and postnatal growth within normal limits; (4) normal head circumference at birth; (5) absence of risk factors such as neonatal asphyxia, prematurity or exposure to teratogenic drugs and (6) negative standard investigations, including comparative genomic hybridization studies, molecular testing for the common expansion mutation in FMR1 and brain CT-scan or MRI. A subset of these NSID patients (n¼11) displayed epilepsy.…”

“…It lies in domain-3 of STXBP1, in close proximity to a previously reported de novo truncating mutation (p.R388X) identified by our group in a patient with NSID and severe epilepsy (Figure 1). 7 Domain-3 together with domain-1 of STXBP1 form the central cavity providing surfaces for Syntaxin-1 binding, an essential step for SNARE complex assembly and subsequent neurotransmitter release. 3,8 No other amino acid altering or splicing mutations were identified in STXBP1 in the remaining patients.…”

“…We previously sequenced STXBP1 in healthy French Canadian controls (n¼190) and did not identify any amino acid changing or splicing mutations. 7 The patient with the c.1206delT (referred to as patient 3) is a man, aged 21 years, born to non-consanguineous French Canadian parents with no family history of developmental disabilities (Table 1). He was delivered at term after an unremarkable pregnancy.…”

“…[3][4][5] Consistent with its important role for neurotransmission, recent studies showed that mutations in STXBP1 cause severe ID and epilepsy. 6,7 Using array genomic hybridization, Saitsu et al 6 identified a de novo 2 Mb deletion encompassing STXBP1 in a patient with Ohtahara syndrome, an infantile form of epileptic encephalopathy characterized by burst suppressions and severe ID. Analysis of candidate genes mapped to the deletion revealed missense mutations in STXBP1 in four other patients with Ohtahara syndrome.…”

“…6 Subsequently, our group reported on the identification of de novo truncating mutations in STXBP1 in two patients with severe non-syndromic ID (NSID) and intractable partial complex epilepsy. 7 In order to better understand the contribution of STXBP1 mutations to NSID, we studied 50 additional patients and identified a novel de novo STXBP1 truncating mutation in a patient with NSID, but surprisingly with no history of epilepsy. This observation indicates that STXBP1 mutations are associated with a wide spectrum of phenotypes, from NSID with or without epilepsy to syndromic forms of epilepsy.…”