The G209A mutation in the alpha-synuclein gene in Brazilian families with Parkinson's disease.

A missense G209A mutation of the alpha-synuclein gene was recently described in a large Contursi kindred with Parkinson's disease (PD). The objective of this study is to determine if the mutation G209A of the alpha-synuclein gene was present in 10 Brazilian families with PD. PD patients were recruited from movement disorders clinics of Brazil. A family history with two or more affected in relatives was the inclusion criterion for this study. The alpha-synuclein G209A mutation assay was made using polymerase chain reaction and the restriction enzyme Tsp45I. Ten patients from 10 unrelated families were studied. The mean age of PD onset was 42.7 years old. We did not find the G209A mutation in our 10 families with PD. Our results suggest that alpha-synuclein mutation G209A is uncommon in Brazilian PD families.

Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis.

Ellis-van Creveld syndrome (EvC, MIM 225500) is an autosomal recessive skeletal dysplasia characterized by short limbs, short ribs, postaxial polydactyly and dysplastic nails and teeth. Congenital cardiac defects, most commonly a defect of primary atrial septation producing a common atrium, occur in 60% of affected individuals. The disease was mapped to chromosome 4p16 in nine Amish subpedigrees and single pedigrees from Mexico, Ecuador and Brazil. Weyers acrodental dysostosis (MIM 193530), an autosomal dominant disorder with a similar but milder phenotype, has been mapped in a single pedigree to an area including the EvC critical region. We have identified a new gene (EVC), encoding a 992-amino-acid protein, that is mutated in individuals with EvC. We identified a splice-donor change in an Amish pedigree and six truncating mutations and a single amino acid deletion in seven pedigrees. The heterozygous carriers of these mutations did not manifest features of EvC. We found two heterozygous missense mutations associated with a phenotype, one in a man with Weyers acrodental dysostosis and another in a father and his daughter, who both have the heart defect characteristic of EvC and polydactyly, but not short stature. We suggest that EvC and Weyers acrodental dysostosis are allelic conditions.

Genomic structure and localization of the human protein phosphatase 2A BRgamma regulatory subunit.

In the course of our analysis of genomic sequence from the human chromosome 4p16.1 region harboring both the Wolfram and Ellis van Creveld syndrome genes we have identified a sequence with high homology (98% at the amino acid level) to the rat cDNA coding for the protein phosphatase 2A BRgamma (PP2ABRgamma) regulatory subunit. Although the human cDNAs for both the BRalpha and BRbeta isoforms have been described previously, the BRgamma subunit has not yet been identified in humans. Here we describe the precise genomic organization and genetic localization of the human PP2ABRgamma gene.

Contig map of the Parkinson's disease region on 4q21-q23.

We have constructed a yeast artificial chromosome contig (YAC) map of human chromosome 4q21-q23 across the Parkinson's disease region by combining molecular and fluorescence in situ hybridization techniques. This map contains 55 YACs and 51 molecular markers, including 23 polymorphic markers. We have also isolated one P1 and 33 bacterial artificial chromosomes located within this contig. Plasmid libraries were generated from 11 of these BAC and P1 clones, and 614 random plasmid clones were sequenced for a total of about 200 kb. This contig allowed us to precisely determine the location of 18 transcripts within the D4S2460-D4S2986 interval, including the alpha-synuclein gene found to be mutated in some families with Parkinson's disease.

Mutation in the alpha-synuclein gene identified in families with Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disorder with a lifetime incidence of approximately 2 percent. A pattern of familial aggregation has been documented for the disorder, and it was recently reported that a PD susceptibility gene in a large Italian kindred is located on the long arm of human chromosome 4. A mutation was identified in the alpha-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype. This finding of a specific molecular alteration associated with PD will facilitate the detailed understanding of the pathophysiology of the disorder.

Evidence for a new spinocerebellar ataxia locus.

The autosomal dominant ataxias (ADA) are a diverse group of multisystem, neurodegenerative disorders characterized by mutations at several chromosomal loci (SCA types 1-5, SCA type 7, DRPLA). We excluded all the known SCA loci by mutational and linkage analyses is an American family of British origin with ADA and document that an additional ataxia locus must exist. The clinical characteristics and ethnic origin of our family are similar to the British Drew family of Walworth with the SCA type 3 mutation and differ from other families without a known ataxia locus. Individuals in our family and the Drew family initially show signs of ataxia but may develop variable degrees of ophthalmoplegia, Parkinsonian features and central demyelination. The phenotypic diversity in families without a known ataxia locus suggests that there may be several other undefined ataxia loci.

Brachydactyly type C gene maps to human chromsome 12q24.

Brachydactyly type C is an autosomal dominant disorder characterized by abnormal segmentation of the index and middle fingers segregating with a high degree of variable expression in members of the same family. We have followed up and studied members of the large kindred segregating with the brachydactyly type C phenotype described by Virgil Haws in 1963, and using genetic linkage analysis, we localized the susceptibility gene to human chromosome 12q24.

Linkage and cytogenetic mapping of a CAG repeat containing human cDNA to 3p24.2-p22.

A trinucleotide (CAG)n repeat containing cDNA was isolated from a human cDNA library and sequenced. The locus was mapped by linkage analysis in the CEPH families and by cytogenetic analysis to 3p24.2-p22. We have additionally excluded this gene as a candidate for small cell lung carcinoma by the analysis of cell lines carrying homozygous deletions for the 3p chromosomal region.

Mapping of a gene for Parkinson's disease to chromosome 4q21-q23.

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease, affecting approximately 1 percent of the population over age 50. Recent studies have confirmed significant familial aggregation of PD and a large number of large multicase families have been documented. Genetic markers on chromosome 4q21-q23 were found to be linked to the PD phenotype in a large kindred with autosomal dominant PD, with a Zmax = 6.00 for marker D4S2380. This finding will facilitate identification of the gene and research on the pathogenesis of PD.

Exclusion of the MSX1 homeobox gene as the gene for the Ellis van Creveld syndrome in the Amish.

Ellis van Creveld syndrome (EVC) is an autosomal recessive disorder which has previously been mapped to human chromosome 4p16.1. This disorder is characterized by disproportionate dwarfism, polydactyly, cleft palate, natal teeth, and congenital heart disease. The MSX1 homeobox gene also maps to the 4p16.1 region. Msx gene transcripts in the mouse embryo are known to be involved in pattern formation of the developing limb bud and craniofacial bones. Thus, on the basis of both map location and known gene function, MSX1 was an excellent candidate as the causative gene for EVC. Nonetheless, direct DNA sequencing of both exons of the MSX1 gene in five affected individuals segregating with the EVC phenotype, as well as those of two obligate carriers, revealed no mutations in the coding region of the gene.

The gene for the Ellis-van Creveld syndrome is located on chromosome 4p16.

Ellis-van Creveld syndrome (EVC) is an autosomal recessive disorder characterized by disproportionate dwarfism, polydactyly, and congenital heart disease. This rare disorder is found with increased frequency among the Old Order Amish community in Lancaster County, Pennsylvania. We have used linkage analysis to localize the gene responsible for the EVC phenotype in nine interrelated Amish pedigrees and three unrelated families from Mexico, Ecuador, and Brazil. We now report the linkage for the Ellis-van Creveld syndrome gene to markers on the distal short arm of human chromosome 4, with Zmax = 6.91 at theta = 0.02 for marker HOX7, in a region proximal to the FGFR3 gene responsible for the achondroplasia phenotype.

Mutations in American families with spinocerebellar ataxia (SCA) type 3: SCA3 is allelic to Machado-Joseph disease.

We identified an expansion of the CAG trinucleotide repeat in the coding region of the Machado-Joseph disease gene in 7 of 24 American families diagnosed with autosomal dominant ataxia. All affected individuals were heterozygous for an expanded allele that ranged from 67 to more than 200 CAG repeats, whereas the normal allele had 14 to 33 repeats. In contrast to the Azorean-Portuguese origins of Machado-Joseph disease, the two largest American families were of German and Dutch-African descent. Clinical, pathologic, and genetic evaluations suggest that American families with spinocerebellar ataxia type 3 differ from those with Machado-Joseph disease by their ethnic origins, predominant spinopontine atrophy, lack of dystonic features, and larger CAG repeat expansion.

The gene for pycnodysostosis maps to human chromosome 1cen-q21.

Pycnodysostosis (OMIM 265800) is an autosomal recessive skeletal disorder first described by Maroteaux and Lamy that is characterized by short stature, increased bone density, delayed closure of cranial sutures, loss of the mandibular angle, dysplastic clavicles, dissolution of the terminal phalanges of the hands and feet, dental abnormalities and increased bone fragility. Patients have a typical appearance secondary to prominence of the calvarium, smallness of the facial features, prominent nose and micrognathia. The French painter, Henri de Toulouse Lautrec (1864-1901), is believed to have had the disorder. Although more than 100 cases have been reported, we are aware of only two large consanguinous pedigrees in which the pycnodysostosis disorder segregates. We have studied the segregation of the pycnodysostosis phenotype in a large consanguinous Mexican pedigree, the clinical features of which are very similar to those described in the Arab pedigree studied by Edelson et al. Here, we report linkage for the pycnodysostosis phenotype in the 1cen-q21 region of human chromosome 1, and discuss candidate genes for this skeletal disorder.