ABSTRACT
No disponible
Subject(s)
Humans , Male , Young Adult , Gastrointestinal Diseases/complications , Appendicitis , Hepatectomy/instrumentation , Hepatectomy/methods , Hepatectomy , Appendectomy/instrumentation , Appendectomy/methods , Appendectomy , Ultrasonography/instrumentation , Ultrasonography/methods , Ultrasonography , Laparoscopy/instrumentation , Laparoscopy/methods , LaparoscopyABSTRACT
BACKGROUND: Mutations in the TRPC6 gene have been reported in six families with adult-onset (17-57 years) autosomal dominant focal segmental glomerulosclerosis (FSGS). Electrophysiology studies confirmed augmented calcium influx only in three of these six TRPC6 mutations. To date, the role of TRPC6 in childhood and adulthood non-familial forms is unknown. METHODS: TRPC6 mutation analysis was performed by direct sequencing in 130 Spanish patients from 115 unrelated families with FSGS. An in silico scoring matrix was developed to evaluate the pathogenicity of amino acid substitutions, by using the bio-physical and bio-chemical differences between wild-type and mutant amino acid, the evolutionary conservation of the amino acid residue in orthologues, homologues and defined domains, with the addition of contextual information. RESULTS: Three new missense substitutions were identified in two clinically non-familial cases and in one familial case. The analysis by means of this scoring system allowed us to classify these variants as likely pathogenic mutations. One of them was detected in a female patient with unusual clinical features: mesangial proliferative FSGS in childhood (7 years) and partial response to immunosupressive therapy (CsA + MMF). Asymptomatic carriers of this likely mutation were found within her family. CONCLUSIONS: We describe for the first time TRPC6 mutations in children and adults with non-familial FSGS. It seems that TRPC6 is a gene with a very variable penetrance that may contribute to glomerular diseases in a multi-hit setting.
Subject(s)
Glomerulosclerosis, Focal Segmental/genetics , TRPC Cation Channels/genetics , Adolescent , Adult , Child , Child, Preschool , DNA Mutational Analysis , Female , Humans , Infant , Middle Aged , TRPC6 Cation Channel , Young AdultSubject(s)
Immunization Programs/statistics & numerical data , Logistic Models , Patient Acceptance of Health Care/statistics & numerical data , Pneumonia, Pneumococcal/prevention & control , Aged , Aged, 80 and over , Bias , Confounding Factors, Epidemiologic , Health Care Surveys , Humans , Pneumococcal Vaccines/administration & dosage , Risk FactorsABSTRACT
BACKGROUND/AIM: Alport syndrome is a hereditary glomerulonephritis, X-linked in 85% of the cases. This form is associated with mutations in the COL4A5 gene which encodes the alpha5 chain of type IV collagen. We have performed the mutational analysis of the COL4A5 gene in a Spanish family with X-linked Alport syndrome. METHODS: We have analyzed three polymorphic markers close to the gene to confirm the X chromosome linkage. By means of the PCR technique, we have screened the 51 exons of the gene. RESULTS: The segregation of the alleles from the analyzed markers was in agreement with the X linkage. Direct sequencing of PCR-amplified products has shown a CCT-to-CTT change in exon 25, resulting in substitution of a proline for a leucine at position 619 of the polypeptide chain (nucleotide 2058). CONCLUSIONS: Although proline is considered a nonconserved amino acid, it is essential, upon hydroxylation, in the maintenance of a stable alpha chain triple-helix collagen. Furthermore, the change cosegregates with the disease in all affected members of the family, not being present in 80 control chromosomes. This represents a new mutation in the COL4A5 gene found in the Spanish population.
