Dermal fibroblasts from nine Marfan syndrome patients with missense mutations in the fibrillin-1 gene (FBN1) produced nearly normal amounts of fibrillin as determined by quantitative pulse-chase experiments. However, six of the seven mutations involving substitutions of highly conserved cysteine residues exhibited lower rates of intracellular transport and secretion. This effect is likely due to improper folding, since intracellular fibrillin processing was also affected by the reducing agent dithiothreitol. Normal secretion patterns were seen in three mutations that either change the conformation of EGF-like domains or change consensus amino acids required for Ca(++)-binding. In all nine fibroblasts strains, however, the deposition of fibrillin in the extracellular matrix was reduced to 50% of normal in two and to less than 30% in seven of the nine samples studied. The protein alterations caused by these missense mutations are associated with moderate to severe features of Marfan syndrome and a dominant negative mechanism is suggested to play a major role in their pathogenesis.
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http://dx.doi.org/10.1093/hmg/2.12.2135 | DOI Listing |
Mol Inform
January 2025
Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstr. 48, 48149, Muenster, Germany.
Primary carnitine deficiency (PCD) is a rare autosomal recessive genetic disorder caused by missense mutations in the SLC22A5 gene encoding the organic carnitine transporter novel type 2 (OCTN2). This study investigates the structural consequences of PCD-causing mutations, focusing on the N32S variant. Using an alpha-fold model, molecular dynamics simulations reveal altered interactions and dynamics suggesting potential mechanistic changes in carnitine transport.
View Article and Find Full Text PDFRadiol Case Rep
March 2025
Department of Obstetrics and Gynecology, Bokoi Tenshi Hospital, N12E3, Higashi-Ku, Sapporo, Hokkaido, 060-0012, Japan.
Fetal cardiac tumors are often the first clinical manifestation of tuberous sclerosis (TS) when fetal ultrasound screening is performed. TS is an autosomal dominant disorder caused by the mutations in or genes. Here we report a case of a patient with a fetal and neonatal cardiac tumor who underwent a genetic analysis for TS after birth.
View Article and Find Full Text PDFBiomed Rep
March 2025
Circulating Biomarkers Laboratory, Pathology Department, Faculty of Medical Sciences, Rio de Janeiro State University, Rio de Janeiro 20550-170, Brazil.
Osteosarcoma (OS) is the most common malignant bone tumor affecting adolescents and young adults and it usually occurs in the long bones of the extremities. The detection of cancer-related genetic alterations has a growing effect in guiding diagnosis, prognosis and targeted therapies. However, little is known about the molecular aspects involved in the etiology and progression of OS, which limits options for targeted therapies.
View Article and Find Full Text PDFNeurodegener Dis Manag
January 2025
Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA.
Friedreich ataxia (FRDA) is a slowly progressive neurological disease resulting from decreased levels of the protein frataxin, a small mitochondrial protein that facilitates the synthesis of iron-sulfur clusters in the mitochondrion. It is caused by GAA (guanine-adenine-adenine) repeat expansions in the gene in 96% of patients, with 4% of patients carrying other mutations (missense, nonsense, deletion) in the gene. Compound heterozygote patients with one expanded GAA allele and a non-GAA repeat mutation can have subtle differences in phenotype from typical FRDA, including, in patients with selected missense mutations, both more severe features and less severe features in the same patient.
View Article and Find Full Text PDFNephrol Dial Transplant
January 2025
Department of Nephrology, Kidney Transplantation and Dialysis, CHU Lille, University of Lille, Lille, France.
Background And Hypothesis: Unlike X-linked or autosomal recessive Alport Syndrome, no clear genotype/phenotype correlation has yet been demonstrated in patients carrying a single variant of COL4A3 or COL4A4.
Methods: We carried out a multicenter retrospective study to assess the risk factors involved in renal survival in patients presenting a single pathogenic variant on COL4A3 or COL4A4.
Results: 97 patients presenting a single pathogenic variant of COL4A3 or COL4A4 were included.
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