Laurie J. Ozelius

The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein

Early-onset torsion dystonia is a movement disorder, characterized by twisting muscle contractures, that begins in childhood. Symptoms are believed to result from altered neuronal communication in the basal ganglia. This study identifies the DYT1 gene on human chromosome 9q34 as being responsible for this dominant disease. Almost all cases of early-onset dystonia have a unique 3-bp deletion that appears to have arisen independently in different ethnic populations. This deletion results in loss of one of a pair of glutamic-acid residues in a conserved region of a novel ATP-binding protein, termed torsinA. This protein has homologues in nematode, rat, mouse and humans, with some resemblance to the family of heat-shock proteins and Clp proteases.

Mutations in the Na+/K+-ATPase α3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism

Rapid-onset dystonia-parkinsonism (RDP, DYT12) is a distinctive autosomal-dominant movement disorder with variable expressivity and reduced penetrance characterized by abrupt onset of dystonia, usually accompanied by signs of parkinsonism. The sudden onset of symptoms over hours to a few weeks, often associated with physical or emotional stress, suggests a trigger initiating a nervous system insult resulting in permanent neurologic disability. We report the finding of six missense mutations in the gene for the Na+/K+ -ATPase alpha3 subunit (ATP1A3) in seven unrelated families with RDP. Functional studies and structural analysis of the protein suggest that these mutations impair enzyme activity or stability. This finding implicates the Na+/K+ pump, a crucial protein responsible for the electrochemical gradient across the cell membrane, in dystonia and parkinsonism.

Genetic linkage of von Recklinghausen neurofibromatosis to the nerve growth factor receptor gene

von Recklinghausen neurofibromatosis (VRNF) is one of the most common inherited disorders affecting the human nervous system. VRNF is transmitted as an autosomal dominant defect with high penetrance but variable expressivity. The disorder is characterized clinically by hyperpigmented patches of skin (café au lait macules, axillary freckles) and by multiple tumors of peripheral nerve, spinal nerve roots, and brain (neurofibromas, optic gliomas). These tumors can cause disfigurement, paralysis, blindness, and death. We have determined the chromosomal location of the VRNF gene by genetic linkage analysis using DNA markers. The VRNF gene is genetically linked to the locus encoding nerve growth factor receptor, located on the long arm of chromosome 17 in the region 17q12----17q22. However, crossovers with the VRNF locus suggest that a mutation in the nerve growth factor receptor gene itself is unlikely to be the fundamental defect responsible for the VRNF phenotype.

The DYT1 phenotype and guidelines for diagnostic testing

Objective: To develop diagnostic testing guidelines for the DYT1 GAG deletion in the Ashkenazi Jewish (AJ) and non-Jewish (NJ) primary torsion dystonia (PTD) populations and to determine the range of dystonic features in affected DYT1 deletion carriers. Methods: The authors screened 267 individuals with PTD; 170 were clinically ascertained for diagnosis and treatment, 87 were affected family members ascertained for genetic studies, and 10 were clinically and genetically ascertained and included in both groups. We used published primers and PCR amplification across the critical DYT1 region to determine GAG deletion status. Features of dystonia in clinically ascertained (affected) DYT1 GAG deletion carriers and noncarriers were compared to determine a classification scheme that optimized prediction of carriers. The authors assessed the range of clinical features in the genetically ascertained (affected) DYT1 deletion carriers and tested for differences between AJ and NJ patients. Results: The optimal algorithm for classification of clinically ascertained carriers was disease onset before age 24 years in a limb (misclassification, 16.5%; sensitivity, 95%; specificity, 80%). Although application of this classification scheme provided good separation in the AJ group (sensitivity, 96%; specificity, 88%), as well as in the group overall, it was less specific in discriminating NJ carriers from noncarriers (sensitivity, 94%; specificity, 69%). Using age 26 years as the cut-off and any site at onset gave a sensitivity of 100%, but specificity decreased to 54% (63% in AJ and 43% in NJ). Among genetically ascertained carriers, onset up to age 44 years occurred, although the great majority displayed early limb onset. There were no significant differences between AJ and NJ genetically ascertained carriers, except that a higher proportion of NJ carriers had onset in a leg, rather than an arm, and widespread disease. Conclusions: Diagnostic DYT1 testing in conjunction with genetic counseling is recommended for patients with PTD with onset before age 26 years, as this single criterion detected 100% of clinically ascertained carriers, with specificities of 43% to 63%. Testing patients with onset after age 26 years also may be warranted in those having an affected relative with early onset, as the only carriers we observed with onset at age 26 or later were genetically ascertained relatives of individuals whose symptoms started before age 26 years.

Mutations in the THAP1 gene are responsible for DYT6 primary torsion dystonia

We report the discovery of a mutation in the THAP1 gene in three Amish-Mennonite families with mixed-onset primary torsion dystonia (also known as DYT6 dystonia). Another mutation in a German family with primary torsion dystonia suggests that THAP1 mutations also cause dystonia in other ancestry groups. We demonstrate that the missense mutation impairs DNA binding, suggesting that transcriptional dysregulation may contribute to the phenotype of DYT6 dystonia.

Positron emission tomographic analysis of the nigrostriatal dopaminergic system in familial Parkinsonism associated with mutations in the Parkin gene

A kindred from South Tyrol (northern Italy) with familial, adult‐onset parkinsonism of pseudo‐dominant inheritance and mutations in the parkin gene was recently described. To gain insight into basal ganglia dysfunction in this form of hereditary parkinsonism, positron emission tomography (PET) with 18‐fluorodopa (FDOPA) and 11C‐raclopride (RAC) was performed in 5 affected family members and 5 asymptomatic relatives with proven compound heterozygous or heterozygous parkin mutations. Results were compared to findings in healthy control subjects and patients with typical sporadic, idiopathic Parkinson‘s disease. Similar to findings in the sporadic Parkinson’s disease group, presynaptic striatal FDOPA storage was decreased in patients with compound heterozygous parkin mutations, with the most prominent reduction in the posterior part of the putamen. Along with the presynaptic lowered FDOPA uptake, we found a uniform reduction of the striatal 11C‐raclopride binding index in all affected family members as compared to asymptomatic family members carrying a heterozygous parkin mutation, sporadic Parkinsons disease, and control subjects. Our PET data provide evidence that parkinsonism in this family is associated with presynaptic dopaminergic dysfunction similar to idiopathic Parkinsons disease pathophysiology, along with alterations at the postsynaptic D2 receptor level. In asymptomatic carriers of a single parkin mutation with an apparently normal allele, we found a mild but statistically significant decrease of mean FDOPA uptake compared to control subjects in all striatal regions. These data indicate a preclinical disease process in these subjects. Ann Neurol 2001;49:367–376

Parkin deletions in a family with adult-onset, tremor-dominant Parkinsonism : Expanding the phenotype

A gene for autosomal recessive parkinsonism, PARK2 (parkin), has recently been identified on chromosome 6q and shown to be mutated in Japanese and European families, mostly with early‐onset parkinsonism. Here we present a large pedigree from South Tyrol (a region of northern Italy) with adult‐onset, clinically typical tremor‐dominant parkinsonism of apparently autosomal dominant inheritance. Haplotype analysis excluded linkage to the chromosome 2p, 4p, and 4q regions that harbor genes associated with autosomal dominant parkinsonism, but implicated the parkin locus on chromosome 6q. Compound heterozygous deletions in the parkin gene (one large and one truncating) were identified in 4 affected male siblings. The patients were clinically indistinguishable from most patients with idiopathic Parkinsons disease. None of them displayed any of the clinical hallmarks described in patients with previously reported parkin mutations, including diurnal fluctuations, benefit from sleep, foot dystonia, hyperreflexia, and early susceptibility to levodopa‐induced dyskinesias. Two affected female individuals carried one (truncating) of the two deletions in a heterozygous state with an apparently normal allele. We conclude that the phenotypic spectrum associated with mutations in the parkin gene is broader than previously reported, suggesting that this gene may be important in the etiology of the more frequent late‐onset typical Parkinsons disease. Ann Neurol 2000;48:65–71

Human Gene for Torsion Dystonia Located on Chromosome 9q32-q34

Torsion dystonia is a movement disorder of unknown etiology characterized by loss of control of voluntary movements appearing as sustained muscle contractions and/or abnormal postures. Dystonic movements can be caused by lesions in the basal ganglia, drugs, or gene defects. Several hereditary forms have been described, most of which have autosomal dominant transmission with variable expressivity. In the Ashkenazi Jewish population the defective gene frequency is about 1/10,000. Here, linkage analysis using polymorphic DNA and protein markers has been used to locate a gene responsible for susceptibility to dystonia in a large, non-Jewish kinship. Affected members of this family have a clinical syndrome similar to that found in the Jewish population. This dystonia gene (ITD1) shows tight linkage with the gene encoding gelsolin, an actin binding protein, and appears by multipoint linkage analysis to lie in the q32-q34 region of chromosome 9 between ABO and D9S26, a region that also contains the locus for dopamine-beta-hydroxylase.

Distribution, type, and origin of Parkin mutations: Review and case studies

Early‐onset Parkinsons disease (PD) has been associated with different mutations in the Parkin gene (PARK2). To study distribution and type of Parkin mutations, we carried out a comprehensive literature review that demonstrated two prominent types of mutations among 379 unrelated mutation carriers: exon rearrangements involving exon 3, 4, or both, and alterations in exons 2 and 7, suggesting mutational hot spots or founders. To elucidate the origin of 14 recurrent Parkin mutations in our samples, we carried out a detailed haplotype analysis at the PARK2 locus. Thirty‐eight mutation‐positive individuals, available family members, and 62 mutation‐negative individuals were genotyped. We determined allele frequencies and linkage disequilibrium (LD) to evaluate the significance of shared haplotypes. We observed no LD between markers at PARK2. Our data support a common founder for the most frequent Parkin point mutation (924C>T; exon 7) and indicate a mutational hot spot as cause of a common small deletion (255/256delA; exon 2). Furthermore, the most frequent Parkin exon deletion (Ex4del) arose independently in 2 of our subjects. However, it also occurred as the result of a founder mutation in 2 cases that shared identical deletion break points. This study provides evidence for both mutational hot spots and founder mutations as a source of recurrent mutations in Parkin, regardless of the mutation type.

Mutations in GNAL cause primary torsion dystonia

Dystonia is a movement disorder characterized by repetitive twisting muscle contractions and postures. Its molecular pathophysiology is poorly understood, in part owing to limited knowledge of the genetic basis of the disorder. Only three genes for primary torsion dystonia (PTD), TOR1A (DYT1), THAP1 (DYT6) and CIZ1 (ref. 5), have been identified. Using exome sequencing in two families with PTD, we identified a new causative gene, GNAL, with a nonsense mutation encoding p.Ser293* resulting in a premature stop codon in one family and a missense mutation encoding p.Val137Met in the other. Screening of GNAL in 39 families with PTD identified 6 additional new mutations in this gene. Impaired function of several of the mutants was shown by bioluminescence resonance energy transfer (BRET) assays.