showing 15 related works from this author
Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial hemiplegic migraine type 2.
2003
Headache attacks and autonomic dysfunctions characterize migraine, a very common, disabling disorder with a prevalence of 12% in the general population of Western countries(1,2). About 20% of individuals affected with migraine experience aura, a visual or sensory-motor neurological dysfunction that usually precedes or accompanies the headache(3). Although the mode of transmission is controversial(4), population-based and twin studies have implicated genetic factors, especially in migraine with aura(5,6). Familial hemiplegic migraine is a hereditary form of migraine characterized by aura and some hemiparesis. Here we show that mutations in the gene ATP1A2 that encodes the alpha2 subunit of t…
Restless legs syndrome: Epidemiological and clinicogenetic study in a South Tyrolean population isolate.
2006
Genetic contributions to restless legs syndrome (RLS) have been consistently recognized from population and family studies. To determine the clinical and genetic features of RLS in a population isolate and explore linkage to three previously described susceptibility loci on chromosomes 12q, 14q, and 9p, respectively, an isolated population in the South Tyrolean Alps was identified and 530 adults participated in the study. Using a two-step strategy, 47 patients with idiopathic RLS were ascertained. The prevalence in the population was 8.9%. Twenty-eight patients (59.6%) had at least one affected first-degree relative and were classified as hereditary cases. In a single extended pedigree, lin…
No evidence of ATP1A2 involvement in 12 multiplex Italian families with benign familial infantile seizures
2005
A missense mutation in the gene encoding the alpha(2) Subunit of the Na+,K+ ATPase pump (ATP1A2) was found in a family with both familial hemiplegic migraine (FHM) and Benign Familial Infantile Seizures (BFIC). As it is still unclear whether ATP1A2 is responsible for pure BFIC syndromes, we checked mutations of the ATP1A2 gene in probands of 12 Italian multiplex families with pure BFIC, who were negative for mutations in the SCN2A gene. We screened the ATP1A2 gene by denaturing high performance liquid chromatography (D-HPLC) and direct sequencing of DNA fragments showing an aberrant elution pattern. We found one exonic variant and five intronic variants, none leading to significant amino ac…
Increased sensitivity of the neuronal nicotinic receptor alpha-2 subunit causes familial epilepsy with nocturnal wandering and ictal fear
2006
Sleep has traditionally been recognized as a precipitating factor for some forms of epilepsy, although differential diagnosis between some seizure types and parasomnias may be difficult. Autosomal dominant frontal lobe epilepsy is characterized by nocturnal seizures with hyperkinetic automatisms and poorly organized stereotyped movements and has been associated with mutations of the α4 and β2 subunits of the neuronal nicotinic acetylcholine receptor. We performed a clinical and molecular genetic study of a large pedigree segregating sleep-related epilepsy in which seizures are associated with fear sensation, tongue movements, and nocturnal wandering, closely resembling nightmares and sleep …
Genetics in restless legs syndrome
2004
Several studies on Restless leas syndrome (RLS) have suggested a substantial genetic contribution in the etiology of this sleep disorder. Clinical surveys of idiopathic RLS patients have shown that up to 60% report a positive family history. Investigations of single families with RLS have suggested an autosomal dominant mode of inheritance with variable expressivity, and some families show possible anticipation. At present, only one twin study is available, showing a high concordance rate (83.3%) between identical twins. Despite several reports suggesting a genetic contribution to the etiology of idiopathic RLS, few molecular genetic studies have been carried out attempting to identify gene…
TBC1D24-TLDc-related epilepsy exercise-induced dystonia: rescue by antioxidants in a disease model
2019
Genetic mutations in TBC1D24 have been associated with multiple phenotypes, with epilepsy being the main clinical manifestation. The TBC1D24 protein consists of the unique association of a Tre2/Bub2/Cdc16 (TBC) domain and a TBC/lysin motif domain/catalytic (TLDc) domain. More than 50 missense and loss-of-function mutations have been described and are spread over the entire protein. Through whole genome/exome sequencing we identified compound heterozygous mutations, R360H and G501R, within the TLDc domain, in an index family with a Rolandic epilepsy exercise-induced dystonia phenotype (http://omim.org/entry/608105). A 20-year long clinical follow-up revealed that epilepsy was self-limited in…
Genome-wide variant calling in reanalysis of exome sequencing data uncovered a pathogenic TUBB3 variant.
2021
Almost half of all individuals affected by intellectual disability (ID) remain undiagnosed. In the Solve-RD project, exome sequencing (ES) datasets from unresolved individuals with (syndromic) ID (n = 1,472 probands) are systematically reanalyzed, starting from raw sequencing files, followed by genome-wide variant calling and new data interpretation. This strategy led to the identification of a disease-causing de novo missense variant in TUBB3 in a girl with severe developmental delay, secondary microcephaly, brain imaging abnormalities, high hypermetropia, strabismus and short stature. Interestingly, the TUBB3 variant could only be identified through reanalysis of ES data using a genome-wi…
Autophagy
2012
Klionsky, Daniel J. et al.
ATP1A2 mutations in 11 families with familial hemiplegic migraine.
2005
Abstract Familial hemiplegic migraine (FHM) is an autosomal dominant form of migraine with aura. The disease is caused by mutations of at least three genes among which two have been identified, CACNA1A and ATP1A2. Very few mutations have been identified so far in ATP1A2. We screened the coding sequence of ATP1A2 in 26 unrelated FHM probands in whom CACNA1A screening was negative. A total of eight different mutations were identified in 11 of the probands (41%), including six missense mutations, one small deletion leading to a frameshift, and one in frame deletion. All were novel mutations. Two mutations were recurrent, in three and two families, respectively. Genotyping of 94 relatives of th…
Elusive amines and cluster headache: mutational analysis of trace amine receptor cluster on chromosome 6q23.
2004
Cluster headache (CH) is characterised by unilateral pain and ipsilateral autonomic features. To date, no molecular genetic evidence has been shown for CH. Small pedigrees and low penetrance render the identification of the CH-gene quite difficult. Nonetheless the association of CH and migraine to a new class of amine, namely trace or elusive amines such as tyramine, octopamine and synephrine, has recently been demonstrated. In particular, in comparison to healthy control subjects, all these neurotransmitters have been found to be greatly elevated in CH sufferers in plasma and platelets both in active and remission periods. A cluster of gene-encoding G-protein-coupled receptors that bind an…
Autosomal dominant hereditary spastic paraplegia: report of a large italian family with R581X spastin mutation
2007
We describe a large kindred with a typical pure form of autosomal dominant hereditary spastic paraplegia (ADHSP). On the basis of maximum LOD score of 1.94 at theta (max)=0 with marker D2S367, we obtained suggestive evidence for linkage of ADHSP to SPG4 locus. Denaturing high-performance liquid chromatography (DHPLC) and direct sequence analysis allowed us to identify a nonsense mutation (1741* C > T) in exon 17 of the Spastin gene. This transition, carried by all the affected family members and two apparently healthy individuals, lead to truncation of the last 36 amino acids in the C-terminus of the protein. These results confirm the existence of mutation in the SPG4 gene with a reduced pe…
Familial hemiplegic migraine type 2 is linked to 0.9Mb region on chromosome 1q23
2003
Familial hemiplegic migraine (FHM) is a rare autosomal dominant disorder characterized by episodes of transient hemiparesis followed by headache. Two chromosomal loci are associated to FHM: FHM1 on chromosome 19 and FHM2 on chromosome 1q21-23. Mutations of the alpha-1A subunit of the voltage gated calcium channel (CACNA1A) are responsible for FHM1. FHM2 critical region spans 28 cM, hence hampering the identification of the responsible gene. Here, we report the FHM2 locus refining by linkage analysis on two large Italian families affected by pure FHM. The new critical region covers a small area of 0.9Mb in 1q23 and renders feasible a positional candidate approach. By mutation analysis, we ex…
De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis di…
2020
International audience; Purpose: Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides-Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies. Other disorders due to SMARCA2 are unknown.Methods: By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS. To stratify variant interpretation, we functionally analyzed SMARCA2 variants in yeasts and performed transcriptomic and genome methylation analyses on blood leukocytes.Results: Of 20 individuals, 14 showed…
A TRAPPC6B splicing variant associates to restless legs syndrome
2016
Abstract INTRODUCTION: RLS is a common movement disorders with a strong genetic component in its pathophysiology, but, up to now, no causative mutation has been reported. METHODS: We re-evaluated the previously described RLS2 family by exome sequencing. RESULTS: We identified fifteen variations in the 14q critical region. The c.485G > A transition of the TRAPPC6B gene segregates with the RLS2 haplotype, is absent in 200 local controls and is extremely rare in 12988 exomes from the Exome Variant Server (EVS). This variant alters a splicing site and hampers the normal transcript processing by promoting exon 3-skipping as demonstrated by minigene transfection and by patient transcripts. CON…
Further evidence of genetic heterogeneity in familial essential tremor.
2007
Familial essential tremor (FET) is a common hereditary movement disorder with phenotypic variability and genetic heterogeneity. To date, linkage analyses revealed three loci associated to essential tremor (ET) (ETM1 on 3q13, ETM2 on 2p22-25, and a locus on 6p23). We performed a genetic analysis of these candidate chromosomal regions in a fifth-generation Italian kindred with autosomal-dominant ET. Of the 22 clinically evaluated family members, nine were affected by ET. The genetic study indicates that the ET in this family is not associated to any of the known ET loci. These findings support evidence of further genetic heterogeneity for such disease. (C) 2007 Elsevier Ltd. All rights reserv…