Microarray-based copy number analysis of neurofibromatosis type-1 (NF1)-associated malignant peripheral nerve sheath tumors reveals a role for Rho-GTPase pathway genes in NF1 tumorigenesis.

Neurofibromatosis type-1 (NF1) is associated with the growth of benign and malignant tumors. Approximately 15% of NF1 patients develop malignant peripheral nerve sheath tumors (MPNSTs), underlining the need to identify specific diagnostic/prognostic biomarkers associated with MPNST development. The Affymetrix Genome-Wide Human single-nucleotide polymorphism (SNP) Array 6.

A meta-analysis of single base-pair substitutions in translational termination codons ('nonstop' mutations) that cause human inherited disease.

'Nonstop' mutations are single base-pair substitutions that occur within translational termination (stop) codons and which can lead to the continued and inappropriate translation of the mRNA into the 3'-untranslated region. We have performed a meta-analysis of the 119 nonstop mutations (in 87 different genes) known to cause human inherited disease, examining the sequence context of the mutated stop codons and the average distance to the next alternative in-frame stop codon downstream, in comparison with their counterparts from control (non-mutated) gene sequences. A paucity of alternative in-frame stop codons was noted in the immediate vicinity (0-49 nucleotides downstream) of the mutated stop codons as compared with their control counterparts (p = 7.

Single base-pair substitutions at the translation initiation sites of human genes as a cause of inherited disease.

A total of 405 unique single base-pair substitutions, located within the ATG translation initiation codons (TICs) of 255 different genes, and reported to cause human genetic disease, were retrieved from the Human Gene Mutation Database (HGMD). Although these lesions comprised only 0.7% of coding sequence mutations in HGMD, they nevertheless were 3.

Identification and molecular characterization of six novel mutations in the UDP-N-acetylglucosamine-1-phosphotransferase gamma subunit (GNPTG) gene in patients with mucolipidosis III gamma.

Mucolipidosis type III (MLIII) is an autosomal recessive disorder affecting lysosomal hydrolase trafficking. In a study of 10 patients from seven families with a clinical phenotype and enzymatic diagnosis of MLIII, six novel GNPTG gene mutations were identified. These included missense (p.

Single base-pair substitutions in exon-intron junctions of human genes: nature, distribution, and consequences for mRNA splicing.

Although single base-pair substitutions in splice junctions constitute at least 10% of all mutations causing human inherited disease, the factors that determine their phenotypic consequences at the RNA level remain to be fully elucidated. Employing a neural network for splice-site recognition, we performed a meta-analysis of 478 disease-associated splicing mutations, in 38 different genes, for which detailed laboratory-based mRNA phenotype assessment had been performed. Inspection of the +/-50-bp DNA sequence context of the mutations revealed that exon skipping was the preferred phenotype when the immediate vicinity of the affected exon-intron junctions was devoid of alternative splice-sites.

Human Gene Mutation Database (HGMD): 2003 update.

The Human Gene Mutation Database (HGMD) constitutes a comprehensive core collection of data on germ-line mutations in nuclear genes underlying or associated with human inherited disease (www.hgmd.org).

Human genetic disease caused by de novo mitochondrial-nuclear DNA transfer.

Transfer of nucleic acid from cytoplasmic organelles to the nuclear genome is a well-established mechanism of evolutionary change in eukaryotes. Such transfers have occurred throughout evolution, but so far, none has been shown unequivocally to occur de novo to cause a heritable human disease. We have characterized a patient with a de novo nucleic acid transfer from the mitochondrial to the nuclear genome, a transfer that is responsible for a sporadic case of Pallister-Hall syndrome, a condition usually inherited in an autosomal dominant fashion.