Abstract: This invention relates to methods for altering the splicing of mRNA in cells. In particular, this invention also relates to methods for increasing the ratio of wild type to misspliced forms of mRNA and corresponding encoded proteins in cells possessing a mutant gene encoding either the i) misspliced mRNA corresponding to the mutant protein or ii) a component in the splicing machinery responsible for processing the misspliced mRNA. In addition, this invention relates to treating individuals having a disorder associated with a misspliced mRNA, such as Familial Dysautonomia or Neurofibromatosis 1, by administering to such an individual a cytokinin such as kinetin.

Abstract: This invention relates to methods and compositions useful for detecting mutations which cause Familial Dysautonomia. Familial dysautonomia (FD; Riley-Day syndrome), an Ashkenazi Jewish disorder, is the best known and most frequent of a group of congenital sensory neuropathies and is characterized by widespread sensory and variable autonomic dysfunction. Previously, we mapped the FD gene, DYS, to a 0.5 cM region of chromosome 9q31 and showed that the ethnic bias is due to a founder effect, with >99.5% of disease alleles sharing a common ancestral haplotype. To investigate the molecular basis of FD, we sequenced the minimal candidate region and cloned and characterized its 5 genes. One of these, IKBKAP, harbors two mutations that can cause FD. The major haplotype mutation is located in the donor splice site of intron 20. This mutation can result in skipping of exon 20 in the mRNA from FD patients, although they continue to express varying levels of wild-type message in a tissue-specific manner.

Abstract: Familial dysautonomia (FD), the Riley-Day syndrome, is an autosomal recessive disorder characterized by developmental loss of neurons from the sensory and autonomic nervous system. It is limited to the Ashkenazi Jewish population, where the carrier frequency is 1 in 30. We have mapped the FD gene to the chromosome region 9q31-q33 by linkage with ten DNA markers in twenty-six families. The maximum lod score of 21.1 with no recombinants was achieved with D9S58. This marker also showed strong linkage disequilibrium with FD, with one allele present on 73% of all affected chromosomes compared to 5.4% of control chromosomes (X2=3142, 15 d.f. p<0.0001). The other nine markers, distributed within 23 cM proximal or distal to D9S58, also yielded significant linkage to FD. D9S53 and D9S105 represent the closest flanking markers for the disease gene. This localization will permit prenatal diagnosis of FD in affected families.

Abstract: The present invention relates to identification of a gene that is inactivated in a mucolipidosis condition. In particular, the invention concerns mutations that disrupt a mucolipin, preferably MCOLN1, in mucolipidosis IV. Recombinant nucleic acids encoding mutant forms of MCOLN1, oligonucleotides specific for such mutations, and diagnostic and therapeutic applications related to these discoveries, are also contemplated.

Abstract: This invention relates to methods and compositions useful for detecting mutations which cause Familial Dysautonomia. Familial dysautonomia (FD; Riley-Day syndrome), an Ashkenazi Jewish disorder, is the best known and most frequent of a group of congenital sensory neuropathies and is characterized by widespread sensory and variable autonomic dysfunction. Previously, we mapped the FD gene, DYS, to a 0.5 cM region of chromosome 9q31 and showed that the ethnic bias is due to a founder effect, with >99.5% of disease alleles sharing a common ancestral haplotype. To investigate the molecular basis of FD, we sequenced the minimal candidate region and cloned and characterized its 5 genes. One of these, IKBKAP, harbors two mutations that can cause FD. The major haplotype mutation is located in the donor splice site of intron 20. This mutation can result in skipping of exon 20 in the mRNA from FD patients, although they continue to express varying levels of wild-type message in a tissue-specific manner.

Abstract: Familial dysautonomia (FD), the Riley-Day syndrome, is an autosomal recessive disorder characterized by developmental loss of neurons from the sensory and autonomic nervous system. It is limited to the Ashkenazi Jewish population, where the carrier frequency is 1 in 30. We have mapped the FD gene to the chromosome region 9q31-q33 by linkage with ten DNA markers in twenty-six families. The maximum lod score of 21.1 with no recombinants was achieved with D9S58. This marker also showed strong linkage disequilibrium with FD, with one allele present on 73% of all affected chromosomes compared to 5.4% of control chromosomes (X2=3142, 15 d.f. p<0.0001). The other nine markers, distributed within 23 cM proximal or distal to D9S58, also yielded significant linkage to FD. D9S53 and D9S105 represent the closest flanking markers for the disease gene. This localization will permit prenatal diagnosis of FD in affected families.

Abstract: Familial dysautonomia (FD), the Riley-Day syndrome, is an autosomal recessive disorder characterized by developmental loss of neurons from the sensory and autonomic nervous system. It is limited to the Ashkenazi Jewish population, where the carrier frequency is 1 in 30. We have mapped the FD gene to the chromosome region 9q31-q33 by linkage with ten DNA markers in twenty-six families. The maximum lod score of 21.1 with no recombinants was achieved with D9S58. This marker also showed strong linkage disequilibrium with FD, with one allele present on 73% of all affected chromosomes compared to 5.4% of control chromosomes (X2=3142, 15 d.f. p<0.0001). The other nine markers, distributed within 23 cM proximal or distal to D9S58, also yielded significant linkage to FD. D9S53 and D9S105 represent the closest flanking markers for the disease gene. This localization will permit prenatal diagnosis of FD in affected families.

Abstract: Familial dysautonomia (FD), the Riley-Day syndrome, is an autosomal recessive disorder characterized by developmental loss of neurons from the sensory and autonomic nervous system. It is limited to the Ashkenazi Jewish population, where the carrier frequency is 1 in 30. We have mapped the FD gene to the chromosome region 9q31-q33 by linkage with ten DNA markers in twenty-six families. The maximum lod score of 21.1 with no recombinants was achieved with D9S58. This marker also showed strong linkage disequilibrium with FD, with one allele present on 73% of all affected chromosomes compared to 5.4% of control chromosomes (X.sup.2 =3142, 15 d.f. p<0.0001). The other nine markers, distributed within 23 cM proximal or distal to D9S58, also yielded significant linkage to FD. D9S53 and D9S105 represent the closest flanking markers for the disease gene. This localization will permit prenatal diagnosis of FD in affected families.