Localization of the gene for rapidly progressive autosomal dominant parkinsonism and dementia with pallido-ponto-nigral degeneration to chromosome 17q21
Localization of the gene for rapidly progressive autosomal dominant parkinsonism and dementia with pallido-ponto-nigral degeneration to chromosome 17q21Mario Wijker1, Zbigniew K. Wszolek2, Eric C. H. Wolters3, Martin A. Rooimans1, Gerard Pals1, Ronald F. Pfeiffer4, Timothy Lynch5, R. L. Rodnitzky6, Kirk C. Wilhelmsen6 and Fré Arwert1,*
1Department of Human Genetics, Free University Amsterdam, v.d. Boechorststraat 7, 1081 BT Amsterdam, The Netherlands, 2Department of Internal Medicine, University of Nebraska, Omaha, NE, USA, 3Graduate School of Neurosciences Amsterdam, Department of Neurology, Academic Hospital Free University Amsterdam, The Netherlands, 4University of Tennessee, Memphis, TN, USA, 5Department of Neurology, Columbia University, New York, USA and 6Division of Neurology, University of Iowa, Iowa City, IA, USA
Received July 14, 1995; Revised and Accepted October 9, 1995
Rapidly progressive autosomal dominant parkinsonism and dementia with pallido-ponto-nigral degeneration (PPND) is a neurodegenerative disorder which begins later in life (>30 years of age) and is characterized by rapidly progressive parkinsonism, dystonia, dementia, perservative vocalizations and pyramidal tract dysfunction. The disease is observed in a large American family that includes almost 300 members in nine generations with 34 affected individuals. In this kindred evidence for linkage to chromosome 17q21 was obtained with a maximum lod score of 9.08 for the D17S958 locus. Multilocus analysis positions the disease gene in an ~10 cM region between D17S250 and D17S943. Notably, the disease locus for a clinically distinct familial neurodegenerative disease named `disinhibition-dementia-parkinsonism-amyotrophy complex' (DDPAC) was recently mapped to the same region of chromosome 17, suggesting that PPND and DDPAC may possibly originate from mutations in the same gene.
We described previously (1 ) a large family presenting with a strikingly uniform picture of an autosomal dominant disease with parkinsonism that responded poorly to anti-parkinsonian medication. Symptoms included progressive parkinsonism, dementia, ocular motility impairment, pyramidal tract dysfunction, frontal lobe release signs, perservative vocalizations and urinary incontinence. Magnetic resonance imaging demonstrated cerebral atrophy affecting predominantly frontal, parietal and temporal lobes, narrowing of the substantia nigra pars compacta, atrophy of the pontine tegmentum (2 ). Dopaminergic functions were investigated with [18F]-L-6-fluorodopa and positron emission tomography demonstrating significantly decreased nigrostriatal activity (3 ). Autopsy findings revealed severe neuronal loss with gliosis in the substantia nigra, pontine and mesencephalic tegmentum and globus pallidus. Plaques, tangles, Lewy bodies and amyloid deposits have not been seen. Immunohistochemically, abundant neurophil threads, complement activated oligodendrocytes and oligodendroglial microtubular masses were found (4 ). The disease shows an unique aggressive course with an onset in the fifth decade and an average duration of 8-9 years after which death, usually caused by aspiration pneumonia, occurs. This family appears to represent a distinct neurodegenerative disease with a characteristic combination of genetic, neuropathological and clinical features.
We employed a linkage mapping approach as a first step towards positional cloning of the pallido-ponto-nigral degeneration (PPND) disease gene and a better understanding of the pathophysiological differences between PPND and other forms of hereditary diseases with parkinsonism.
Our findings indicate that the PPND locus maps to chromosome 17q, in the same region where a distinct neurological disease (disinhibition-dementia-amyotrophy complex; DDPAC) gene has been localized (5 ).
The PPND family contains 34 affected individuals over nine generations and has been described (1 ,6 ). One of us (Z.K.W.) investigated all the living patients and most of their sibs. An individual was diagnosed as affected based on the presence of parkinsonism, personality change and/or dementia.
The age of onset of the disease varies from 32 to 58 years. We estimate that the disease penetrance in this pedigree is 15% by age 40, 80% by age 45 and >90% after 50.
Blood samples from 182 family members including 15 affected individuals were obtained (Fig. 1 ). We selected 27 individuals that would be most informative for our linkage study. The average age of phenotypically healthy sibs included in this study was 49 years, so we assumed a penetrance of 90%. The youngest generation was not included since no patients were observed yet.
Our initial linkage studies focused on a few candidate regions. Markers located close to the prion-like protein on the short arm of chromosome 20, close to the dopamine D2 receptor on chromosome 11q and markers covering 90% of chromosome 4p were tested, but none of them suggested linkage.
Subsequently, we started a systematic genome search with polymorphic microsatellite markers evenly distributed over the human autosomes with an average distance of ~20 cM. Computer simulation showed that the maximum LOD score for a 10% linked marker (assuming four equally frequent alleles) was >4.
Over 70 microsatellite markers were typed before linkage was detected with markers mapping to the long arm of chromosome 17. Two point maximum likelihood calculations between D17S579 and the disease phenotype resulted in a highly significant lod score of 8.36 at [theta] = 0.
Table 1 summarizes the two point maximum likelihood data between chromosome 17q markers [D17S798 (7 cM) D17S946 (0.1 cM) D17S250 (1.8 cM) THRAI (3.8 cM) D17S800 (1 cM) D17S579 (1 cM) HOX2B (1 cM) D17S791 (3 cM) D17S958 (1 cM) D17S943 (3 cM) D17S941 (1 cM) D17S788] and the PPND locus. Order of loci and recombination frequencies were taken from the Genome Database (Johns Hopkins University).
Haplotypes defined by loci listed in Table 1 are shown in Figure 1 .
Multipoint analysis using adjacent pairs of marker loci resulted in a multilocus lod score of 10.8 (Fig. 2 ). Haplotype analysis places the PPND locus between the loci D17S250 and D17S943.
The PPND family, as previously described (1 ), was clinically evaluated by Z.K.W. At the time of evaluation peripheral blood samples were obtained for establishment of EBV-transformed cell lines and DNA extraction.
Genomic DNA was isolated by standard proteinase K digestion, phenol/chloroform extraction and isopropanol precipitation. Analysis of simple sequence CA-repeat markers was performed using published nucleotide primer sequences (10 ). Microsatellite markers were obtained from the Dutch Microsatellite Marker Collection (established by The Netherlands Organisation of Scientific Research). Markers were selected for spanning the whole genome with ~20 cM spacing. PCR reactions were carried out in 15 [mu]l and 1.7 [mu]M fluorescein-12-dUTP (Boehringer Mannheim) was added. Concentrations dATP, dCTP, dGTP were 200 [mu]M and dTTP was 50 [mu]M. PCR products were separated on 6% polyacrylamide/7 M urea (Biozym) using the A.L.F. sequencer (Pharmacia LKB Biotechnology). The Fragment Manager software version 1.1 (Pharmacia LKB Biotechnology) was used to analyse the data (11 ). The sizer 50-500 (Pharmacia Biotech) and internal PCR markers were used to calculate exact allele length.
The MLINK and the LINKMAP routine of the LINKAGE package (version 5.1) were used to calculate pairwise lod scores and perform multilocus analysis. PPND was deemed to have autosomal dominant inheritance with a disease frequency of 0.000001 and a penetrance of 90%. No new mutations were allowed and no different recombination rates between male and female were used. Allele frequencies and (sex averaged) recombination frequencies between loci were taken from the Genome Database (Johns Hopkins University, G00-270-726, G00-355-556) and the recent literature (12 -14 ). However, one must consider a relatively high female/male recombination frequency ratio in this chromosomal subregion. A ratio of 2 has been used between D17S588 and D17S74 based on data reported by Devilee et al. (15 ).
We would like to thank Dr L. P. ten Kate for his comments and Dr R. R. Frants (University of Leiden) for his support during the initial stage of this study. Financial support provided by `Stichting Bevordering Neurologisch Onderzoek Amsterdam' is gratefully acknowledged. We also thank Ms Y. van Oers for her technical assistance and the PPND family for their interest and cooperation throughout this study.
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