A chromosome 4p haplotype segregating with Parkinson's disease and postural tremor

Farrer, Matthew J.; Gwinn‐Hardy, Katrina; Muenter, Manfred D.; DeVriéze, Fabienne Wavrant; Crook, Richard; Pérez‐Tur, Jordi; Lincoln, Sarah; Maraganore, Demetrius M.; Adler, Charles H.; Newman, Stephanie; MacElwee, Kari; McCarthy, Page; Miller, Carol A.; Waters, Cheryl; Hardy, John

doi:10.1093/hmg/8.1.81

Cited by 245 publications

(126 citation statements)

References 29 publications

Supporting

Mentioning

118

Contrasting

Unclassified

Order By: Relevance

“…These observations suggest that HTRA2 has a causal role in essential tremor and in the subset of Parkinson disease preceded by essential tremor. Among essential tremor patients generally, the incidence of Parkinson disease is increased four-to fivefold, and essential tremor and Parkinson disease have been observed in the same families (33)(34)(35). We speculate that casecontrol studies of that subset of Parkinson disease preceded by essential tremor would reveal associations with functional missense alleles of HTRA2.…”

Section: Discussionmentioning

confidence: 84%

Mitochondrial serine protease HTRA2 p.G399S in a kindred with essential tremor and Parkinson disease

Gulsuner

Gülsüner

Mercan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

120

View full text Add to dashboard Cite

Essential tremor is one of the most frequent movement disorders of humans and can be associated with substantial disability. Some but not all persons with essential tremor develop signs of Parkinson disease, and the relationship between the conditions has not been clear. In a six-generation consanguineous Turkish kindred with both essential tremor and Parkinson disease, we carried out whole exome sequencing and pedigree analysis, identifying HTRA2 p.G399S as the allele likely responsible for both conditions. Essential tremor was present in persons either heterozygous or homozygous for this allele. Homozygosity was associated with earlier age at onset of tremor (P < 0.0001), more severe postural tremor (P < 0.0001), and more severe kinetic tremor (P = 0.0019). Homozygotes, but not heterozygotes, developed Parkinson signs in the middle age. Among population controls from the same Anatolian region as the family, frequency of HTRA2 p.G399S was 0.0027, slightly lower than other populations. HTRA2 encodes a mitochondrial serine protease. Loss of function of HtrA2 was previously shown to lead to parkinsonian features in motor neuron degeneration (mnd2) mice. HTRA2 p. G399S was previously shown to lead to mitochondrial dysfunction, altered mitochondrial morphology, and decreased protease activity, but epidemiologic studies of an association between HTRA2 and Parkinson disease yielded conflicting results. Our results suggest that in some families, HTRA2 p.G399S is responsible for hereditary essential tremor and that homozygotes for this allele develop Parkinson disease. This hypothesis has implications for understanding the pathogenesis of essential tremor and its relationship to Parkinson disease.gene identification | neurodegenerative disease | mitochondrial dysfunction | DNA sequencing | mutation

show abstract

Section: Discussionmentioning

confidence: 84%

Mitochondrial serine protease HTRA2 p.G399S in a kindred with essential tremor and Parkinson disease

Gulsuner

Gülsüner

Mercan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

120

View full text Add to dashboard Cite

show abstract

“…The causative gene has not yet been identified for all of the loci, nor do all of the identified genes contain causative or disease-determining mutations (i.e., variations in some of these genes are considered genetic risk factors increasing the risk to develop PD rather than being a sufficient cause). Finally, one locus, PARK4, was designated as a novel chromosomal region associated with PD (Farrer et al 1999;Singleton et al 2003) but was later found to be identical with PARK1 (SNCA-associated PD) (Singleton et al 2003). It is noteworthy that some of the loci have been identified by genetic linkage analysis in large families, some based on the known function of the protein product of the gene they contain, yet others have been established by genomewide association studies performed on a population level.…”

Section: Genetic Classification Of Pdmentioning

confidence: 99%

Genetics of Parkinson's Disease

Klein

Westenberger

2012

Cold Spring Harbor Perspectives in Medicine

1,113

780

View full text Add to dashboard Cite

Fifteen years of genetic research in Parkinson's disease (PD) have led to the identification of several monogenic forms of the disorder and of numerous genetic risk factors increasing the risk to develop PD. Monogenic forms, caused by a single mutation in a dominantly or recessively inherited gene, are well-established, albeit relatively rare types of PD. They collectively account for about 30% of the familial and 3%-5% of the sporadic cases. In this article, we will summarize the current knowledge and understanding of the molecular genetics of PD. In brief, we will review familial forms of PD, basic genetic principles of inheritance (and their exceptions in PD), followed by current methods for the identification of PD genes and risk factors, and implications for genetic testing.

show abstract

“…This locus on chromosome 4p14-16.3 was described in 1999, in six generations family with early-onset autosomal dominant, rapidly progressive and levodopa-responsive PD with atypical features more like as Lewy body disease [56] manifesting segregation with essential tremor and sharing the same haplotype. The triplication of the locus containing α-synuclein [57] correspond au locus PARK1.…”

Section: Park4mentioning

confidence: 99%

Mechanisms Implicated in Parkinson Disease from Genetic Perspective

Popescu¹

2016

Med Clin Rev

View full text Add to dashboard Cite

Parkinson's disease (PD) etiology is based upon interactions between genetic susceptibility and the environmental exposure. Multiple environmental factors inducing oxidative stress, mitochondrial damage, impairment of the neuroprotective and autophagic mechanisms are responsible for dopaminergic neurons death. Defining the contributions of genetic and environmental factors, may have important implications for understanding the pathogenesis of PD. The linkage analysis in Mendelian forms of PD especially in multiplex highly penetrant families is essential to elucidate biological mechanisms for PD susceptibility. Concerning the monogenic forms of PD were found mutations in 7 genes of AD transmission (SNCA, LRRK2, GIGYF2, VPS35, EIF4G1, HTRA2, TMEM230) and even more in those of AR transmission. This review aims to give an overview of the existing evidence of multiples molecular pathways involving cytoplasmic organelles' function, neurodevelopmental mechanisms, synaptic vesicles endocytosis and trafficking, maintaining the integrity of the cytoskeleton and axonal transport in neurons. Understanding the molecular mechanisms following the identification of genes mutations and low-penetrance susceptibility alleles in familial and sporadic PD patients by genotyping technology and functional studies represent an essential step for the development of adequate biomarkers and potent therapies.

show abstract

A chromosome 4p haplotype segregating with Parkinson's disease and postural tremor

Cited by 245 publications

References 29 publications

Mitochondrial serine protease HTRA2 p.G399S in a kindred with essential tremor and Parkinson disease

Mitochondrial serine protease HTRA2 p.G399S in a kindred with essential tremor and Parkinson disease

Genetics of Parkinson's Disease

Mechanisms Implicated in Parkinson Disease from Genetic Perspective

Contact Info

Product

Resources

About