Personal ViewDeciphering the role of heterozygous mutations in genes associated with parkinsonism
Introduction
Identification of several monogenic forms has established that parkinsonism is a multifactorial disorder that has an unambiguous genetic cause in a subset of patients. Genetic mutations can be detected in about 3% of patients with parkinsonism,1 but the proportion can be as high as 77% in groups of patients selected for age at onset, positive family history,2 and ethnic origin.3, 4 Inheritance of the most common familial forms of parkinsonism is thought to be autosomal dominant in the case of LRRK2 (leucine-rich repeat kinase 2; also known as PARK8) or recessive in the cases of parkin (also known as PARK2) and PINK1 (PTEN-induced putative kinase 1; also known as PARK6). However, in 2000, researchers began to question the simple applicability of these established mendelian concepts to the inheritance of parkinsonism.2 At that time, experience from large studies that screened for mutations in recessively inherited parkin first revealed that more than half of the affected patients had only one mutated allele (rather than the expected two). Similar observations were later reported for PINK1. Conversely, most people carrying a single mutation in the dominantly transmitted LRRK2 gene are clinically unaffected. In this article we discuss the role of heterozygous LRRK2 mutations in the development of parkinsonism and provide the first review of the debated role of heterozygous mutations in the putative recessive genes parkin and PINK1. We have taken into account results from mutation analyses in patients, family members, and controls, and findings from clinical, neuroimaging, and electrophysiological studies in mutation carriers. We have integrated these findings into a hypothetical model of parkinsonism as a complex disorder. We also discuss the implications of heterozygosity in the development of guidelines for genetic testing of patients with parkinsonism, for the counselling of mutation carriers, and for a better understanding of disease pathogenesis.
Section snippets
Monogenic forms of parkinsonism
Six genes associated with parkinsonism were localised after linkage analysis in large families: mutations have been identified in SNCA (α-synuclein; also known as PARK1),5 parkin,6 PINK1,7 DJ1 (also known as PARK7),8 LRRK2,9, 10 and ATP13A2 (ATPase type 13A2; also known as PARK9).11 Although the identification of dominantly inherited mutations in SNCA, the first gene to be associated with heritable parkinsonism, have revolutionised our understanding of the causes of this disorder and have given
Mutations and mechanisms
LRRK2 was identified in 2004 by two independent groups,9, 10 and LRRK2 mutations are now recognised as the most common cause of genetic parkinsonism. Mutations in LRRK2 are mostly, but not exclusively,22, 32, 34 associated with a classic parkinsonism-like phenotype with onset at age 50–70 years.33, 35, 36 LRRK2 is a large gene of 51 exons; it encodes the 2527-aminoacid-residue protein LRRK2 (also known as dardarin), which contains various conserved domains.9, 10 There are more than 50 variants
Mutations and mechanisms
Homozygous or compound heterozygous mutations in the recessive parkinsonism genes parkin and PINK1 are unequivocally associated with heritable parkinsonism and early age at onset. However, penetrance might be reduced in isolated cases, as suggested by a recent report of a neurologically unaffected carrier of a compound heterozygous parkin mutation at age 56 years;59 alternatively, penetrance in recessive genes might be age dependent, and expression of the parkinsonism phenotype might simply be
Statement of hypothesis
Like many ageing-associated conditions, such as coronary heart disease and Alzheimer's disease, classic parkinsonism is a complex disorder. As such, it encompasses a syndrome that has numerous causes. Different genes by themselves, alleles working in synergy, or genetic traits together with environmental contributors can produce highly similar phenotypes (ie, phenocopies). According to this model, cumulative genetic and environmental factors of greater severity will result in onset of the
Future perspectives
Irrespective of the allele in question or the mode of its inheritance, the penetrance and expressivity of heterozygous gene mutations have far-reaching implications for patient care and Parkinson's disease research alike. First, techniques for clinical and laboratory screening of patients and controls need to be improved. In the clinical setting, particular emphasis should be placed on minor motor signs; rating scales might need to be adapted (or newly designed) to represent subtle changes in
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