Investigating the effect of 28 BRCA1 and BRCA2 mutations on their related transcribed mRNA.

Germline inactivating mutations in the BRCA1 and BRCA2 genes are responsible for hereditary breast and ovarian cancer syndrome (HBOCS). Genetic testing of these genes identifies a significant proportion of variants of uncertain significance (VUS). Elucidation of the clinical impact of these variants is an important challenge in genetic diagnostics and counseling.

Identification of two novel KIF5A mutations in hereditary spastic paraplegia associated with mild peripheral neuropathy.

Spastic paraplegia type 10 (SPG10) is a rare form of autosomal dominant hereditary spastic paraplegia (AD-HSP) due to mutations in KIF5A, a gene encoding the neuronal kinesin heavy-chain involved in axonal transport. KIF5A mutations have been associated with a wide clinical spectrum, ranging from pure HSP to isolated peripheral nerve involvement or complicated HSP phenotypes. Most KIF5A mutations are clustered in the motor domain of the protein that is necessary for microtubule interaction.

The transmembrane activator TACI triggers immunoglobulin class switching by activating B cells through the adaptor MyD88.

BAFF and APRIL are innate immune mediators that trigger immunoglobulin G (IgG) and IgA class-switch recombination (CSR) in B cells by engaging the receptor TACI. The mechanism that underlies CSR signaling by TACI remains unknown. Here we found that the cytoplasmic domain of TACI encompasses a conserved motif that bound MyD88, an adaptor that activates transcription factor NF-kappaB signaling pathways via a Toll-interleukin 1 (IL-1) receptor (TIR) domain.

SR proteins and the nonsense-mediated decay mechanism are involved in human GLB1 gene alternative splicing.

Background: The human GLB1 gene is known to give rise to two alternatively spliced mRNAs, which encode two different proteins: lysosomal beta-galactosidase (beta-gal) and elastin-binding protein (EBP). The beta-gal transcript includes the 16 exons of the GLB1 gene. In the EBP transcript, exons 3, 4 and 6 are skipped, while exon 5 has a different reading frame.

Laparoscopic duodenal-jejunal exclusion in the treatment of type 2 diabetes mellitus in patients with BMI<30 kg/m2 (LBMI).

Background: The association between medical and dietetic-behavioral treatments of type 2 diabetes mellitus (T2DM) has demonstrated to have variable results. The surgical treatment of T2DM is justifiable after the observation of a successful glycemic control in patients submitted to Roux-en-Y gastric bypass and biliopancreatic diversion. Experiments have shown an important role of the proximal intestine in glycemia decrease and diabetes control.

Haplotype analysis suggests a single Balkan origin for the Gaucher disease [D409H;H255Q] double mutant allele.

Gaucher disease is an autosomal recessive lysosomal storage disease that is mainly due to mutations in the GBA gene. Most of the mutant alleles described so far bear a single mutation. However, there are a few alleles bearing two or more DNA changes.

Serial magnetic resonance imaging and neurophysiological studies in multiple sulphatase deficiency.

We present serial clinical, magnetic resonance imaging (MRI) and neurophysiological findings of a patient with multiple sulphatase deficiency (MSD), who was first admitted at the age of 9 months, because of psychomotor retardation. MRI demonstrated extensive diffuse symmetrical high signal in the deep white matter of both cerebral hemispheres, as well as of the subcortical white matter and the brainstem, while there was additional enlargement of sulci and subdural spaces and mild atrophy. Assay of arylsulphatase A activity in white blood cell homogenates at the age of 29 months disclosed a marked deficiency of the enzyme, compatible with the diagnosis of early-infantile metachromatic leukodystrophy.

Expression and characterization of 14 GLB1 mutant alleles found in GM1-gangliosidosis and Morquio B patients.

GM1-gangliosidosis and Morquio B disease are lysosomal storage disorders caused by beta-galactosidase deficiency attributable to mutations in the GLB1 gene. On reaching the endosomal-lysosomal compartment, the beta-galactosidase protein associates with the protective protein/cathepsin A (PPCA) and neuraminidase proteins to form the lysosomal multienzyme complex (LMC). The correct interaction of these proteins in the complex is essential for their activity.

Twenty-one novel mutations in the GLB1 gene identified in a large group of GM1-gangliosidosis and Morquio B patients: possible common origin for the prevalent p.R59H mutation among gypsies.

GM1-gangliosidosis and Morquio B disease are rare lysosomal storage disorders caused by beta-galactosidase deficiency due to mutations in the GLB1 gene. Three major clinical forms of GM1-gangliosidosis have been established on the basis of age of onset and severity of symptoms: infantile, late infantile/juvenile, and adult. We performed mutation analysis on 30 GM1-gangliosidosis and five Morquio B patients, mainly of Spanish origin, and all the causative mutations were identified.

Homozygosity for the double D409H+H255Q allele in type II Gaucher disease.

Homozygosity for D409H has been associated with a unique type III subtype of the disease with a phenotype dominated by severe cardiovascular involvement, whereas neurological findings, if present, are restricted to oculomotor apraxia and features such as visceromegaly are either minimal or absent. Using PCR amplification followed by restriction enzyme analysis, 3 patients (1 Greek, 2 Albanians) were IDentified with the D409H/D409H genotype. All shared a very severe early-onset neurological phenotype that classified them as type II.

Clinical and mutational characterization of three patients with multiple sulfatase deficiency: report of a new splicing mutation.

Multiple sulfatase deficiency (MSD) is a rare autosomal recessive lysosomal storage disease characterized by impaired activity of all known sulfatases. The gene SUMF1, recently identified, encodes the enzyme responsible for post-translational modification of a cysteine residue, which is essential for the activity of sulfatases. Fewer than 30 MSD patients have been reported to date and 23 different mutations in the SUMF1 gene have been identified.

Perinatal lethal phenotype with generalized ichthyosis in a type 2 Gaucher disease patient with the [L444P;E326K]/P182L genotype: effect of the E326K change in neonatal and classic forms of the disease.

Gaucher disease, the most common lysosomal storage disorder, encompasses a wide spectrum of clinical symptoms. The perinatal lethal form is very rare and is considered a distinct form of classic type 2 Gaucher disease. Prominent features of the severe perinatal form are hepatosplenomegaly variable, associated with hydrops fetalis and ichthyosis.

A mutation within the saposin D domain in a Gaucher disease patient with normal glucocerebrosidase activity.

Only two Gaucher disease (GD) patients bearing mutations in the prosaposin gene (PSAP), and not in the glucocerebrosidase gene (GBA), have been reported. In both cases, one mutant allele remained unidentified. We report here the identification of the second mutation in one of these patients, being the first complete genotype described so far in a SAP-C-deficient GD patient.