Biomedical subjects

Pierre Szepetowski

Publications and source records attributed to Pierre Szepetowski.

5 recordsLinked to original sources

PubMed2002

New human sodium/glucose cotransporter gene (KST1): identification, characterization, and mutation analysis in ICCA (infantile convulsions and choreoathetosis) and BFIC (benign familial infantile convulsions) families.

Cotransporters represent a major class of proteins that make use of ion gradients to drive active transport of substrate into cells. A new human gene, KST1, encoding a member of the sodium/glucose cotransporter family, was identified onto human chromosome 16p12-p11. This genomic region contains a major gene responsible for a syndrome of infantile convulsions and paroxysmal dyskinesia (ICCA syndrome), inherited as an autosomal dominant trait, as well as for benign familial infantile convulsions (BFIC). The entire coding sequence of the human KST1 gene was determined using a combination of methods including in silico comparison of its rabbit orthologous DNA complementary to RNA (cDNA) to the corresponding human genomic sequences, reverse transcription-polymerase chain reaction on human brain RNA, 5' and 3' rapid amplification of cDNA ends. The gene is divided into 16 exons and the predicted protein of 675 amino acids contains 14 transmembrane domains. It shares significant homology to the sodium-glucose transporter 1 cotransporter proteins. An alternatively spliced transcript resulting from the skipping of exon 6 led to a predicted protein lacking the 4th transmembrane domain. As ion transporters are good candidates for a large variety of human diseases, including paroxysmal disorders, a mutation search was performed in four families with ICCA or BFIC syndromes. No pathogenic mutation was found, although several polymorphic variants with amino acids exchanges were identified. Due to its broad expression in human tissues, the human KST1 gene could be involved in several other diseases mapped to human chromosome 16p12-p11.

Amino Acid Sequence↗

PubMed2002

Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse.

The Charcot-Marie-Tooth (CMT) disorders comprise a group of clinically and genetically heterogeneous hereditary motor and sensory neuropathies, which are mainly characterized by muscle weakness and wasting, foot deformities, and electrophysiological, as well as histological, changes. A subtype, CMT2, is defined by a slight or absent reduction of nerve-conduction velocities together with the loss of large myelinated fibers and axonal degeneration. CMT2 phenotypes are also characterized by a large genetic heterogeneity, although only two genes---NF-L and KIF1Bbeta---have been identified to date. Homozygosity mapping in inbred Algerian families with autosomal recessive CMT2 (AR-CMT2) provided evidence of linkage to chromosome 1q21.2-q21.3 in two families (Zmax=4.14). All patients shared a common homozygous ancestral haplotype that was suggestive of a founder mutation as the cause of the phenotype. A unique homozygous mutation in LMNA (which encodes lamin A/C, a component of the nuclear envelope) was identified in all affected members and in additional patients with CMT2 from a third, unrelated family. Ultrastructural exploration of sciatic nerves of LMNA null (i.e., -/-) mice was performed and revealed a strong reduction of axon density, axonal enlargement, and the presence of nonmyelinated axons, all of which were highly similar to the phenotypes of human peripheral axonopathies. The finding of site-specific amino acid substitutions in limb-girdle muscular dystrophy type 1B, autosomal dominant Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy type 1A, autosomal dominant partial lipodystrophy, and, now, AR-CMT2 suggests the existence of distinct functional domains in lamin A/C that are essential for the maintenance and integrity of different cell lineages. To our knowledge, this report constitutes the first evidence of the recessive inheritance of a mutation that causes CMT2; additionally, we suggest that mutations in LMNA may also be the cause of the genetically overlapping disorder CMT2B1.

Algeria↗

PubMed2002

Clinical and genetic analysis of a new multigenerational pedigree with GEFS+ (Generalized Epilepsy with Febrile Seizures Plus).

Febrile seizures affect 2-5% of all children younger than 6 years. A small proportion of children with febrile seizures later develop epilepsy. The syndrome of generalized epilepsy with febrile seizures plus (GEFS+) is a heterogeneous disorder characterized by febrile seizures that may persist beyond age 6 years and nonfebrile seizures. Several genes have been localized for FS by linkage analysis, and three GEFS+ genes (SCN1A, SCN1B, GABRG2) have been identified. We identified a large multigenerational family with GEFS+ in France. All affected members had FSs. Among them, seven had other types of epileptic seizures including FSs after age 6 years, nonfebrile generalized seizures, or partial seizures later in life. Genetic linkage study excluded the candidate genes and loci for FS and GEFS+, thus proving the existence of a new GEFS+ genetic locus underlying the phenotype observed in this family.

Adolescent↗

PubMed2002

Benign familial infantile seizures: further delineation of the syndrome.

Benign familial infantile seizures are an autosomal dominant epilepsy disorder that is characterized by convulsions, with onset at age 3 to 12 months and a favorable outcome. Benign familial infantile seizures have been linked to chromosome 19q whereas infantile convulsions and choreoathetosis syndrome, in which benign familial infantile seizure is associated with paroxysmal choreoathetosis, has been linked to chromosome 16p 12-q12. Many additional families from diverse ethnic backgrounds have similar syndromes that have been linked to the chromosome 16 infantile convulsions and choreoathetosis syndrome region. Moreover, in one large pedigree with paroxysmal kinesiogenic dyskinesias only, the syndrome has also been linked to the same genomic area. Families with pure benign familial infantile seizures may be linked to chromosome 16 as well. In this study, we present a series of 19 families and 24 otherwise healthy infants with benign familial infantile seizures. Two of these families include members affected with benign familial infantile seizures and paroxysmal choreoathetosis. We included patients with normal neurologic examinations, who started having simple partial seizures, complex partial seizures, or apparently generalized seizures without recognized etiology between 2 months and 2 years of age. Neurologic studies were normal, but in all patients, there was a history of similar seizures and age at onset in either the father or the mother. Twenty-four patients (14 girls and 10 boys) were evaluated at our hospital between February 1990 and February 2001. Age at onset, sex, family history of epilepsy and/or paroxysmal dyskinesias, neurologic examination, semiology, distribution, and frequency and duration of seizures were evaluated. Electroencephalographic (EEG) and neuroradiologic studies were also performed. Seizures began between 3 and 22 months of life, with a median age of 5 1/2 months. Nine patients (37.5%) had only apparently generalized seizures, 5 patients (20.8%) had only partial seizures, and 10 patients had both partial and apparently generalized seizures (41.6%). Seizures were invariably brief, occurred during the waking state (100%), and presented mainly in clusters in 12 patients (50%). Interictal EEG was normal in 23 patients (95.8%). Sixteen patients (66.6%) had a confirmed history of convulsions in family members other than parents. Twenty-two patients became seizure free after 30 months of life. Two brothers in the same family had brief paroxysmal episodes of choreoathetosis in the hemibody triggered by stress while awake at 15 and 17 years old, respectively. One of them had paroxysmal choreoathetosis only, and the other was associated with benign familial infantile seizures. One father had brief spontaneous episodes of paroxysmal choreoathetosis when awake at age 18 years. All of them had a good response to antiepilepsy drugs, and neurologic examination and EEG and neuroradiologic studies were normal. Benign familial infantile seizure is a genetic epilepsy syndrome with autosomal dominant inheritance. It may be associated with paroxysmal choreoathetosis (infantile convulsions and choreoathetosis syndrome), which has been linked to the chromosome 16 infantile convulsions and choreoathetosis syndrome region. Patients in families with infantile convulsions and choreoathetosis syndrome could display either benign familial infantile seizures or paroxysmal choreoathetosis or both. It is likely that the disease in families with pure benign familial infantile seizures may be linked to the infantile convulsions and choreoathetosis region as well. We cannot exclude the possibility that the youngest patients may develop choreoathetosis or other dyskinesias later in life.

Athetosis↗

PubMed2002

Epilepsy and ionic channels.

Ion channels play critical roles in a broad range of physiological processes. In particular, they represent a common basis for the excitable properties of different tissues. Consequently, ion channels of many different types have been implicated in several human genetic disorders of the heart, brain and skeletal muscle. An increasing number of genes encoding neurotransmitter- or voltage-gated ion channel subunits have proved to be mutated in various idiopathic human epilepsies as well as in different animal models. The epilepsies could thus be considered as one of many paroxysmal disorders that are due to mutations in ion channel genes, the so-called channelopathies. However, recent data supported the hypothesis that other genes with different properties could also be responsible for human idiopathic epilepsies, thus opening new and exciting areas of research. Effort is still needed to identify the genes responsible for the large variety of other epileptic disorders inherited as Mendelian traits and evaluate the role of these genes in the more common and polygenic forms. Defining the genetic bases of the latter will also require that exhaustive association studies are performed. These studies may help understand the pathophysiology of human epilepsies and represent the first step towards the discovery of new therapeutic targets, as exemplified in the case of the KCNQ potassium channels.

Cerebral Cortex↗