Prevalence and Clinical Features of LRRK2 Mutations in Patients with Parkinson Disease

Review Article


Pilar Gómez‐Garre ¹, Fátima Carrillo 1 and Pablo Mir ^{1 2}

Affiliations: ¹Unidad de Trastornos del Movimiento, Servicio de Neurologıa y Neurofisiologıa Clınica, Instituto de Biomedicina de Sevilla, Hospital Universitario
Virgen del Rocıo/CSIC/Universidad de Sevilla, Seville, Spain and ²Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain

ABSTRACT

In recent years, 16 PARK loci have been reported to be associated with Parkinson disease (PD). The genes in nine of these PARK loci have already been identified. To date, mutations in LRRK2 (PARK8) are the most common genetic determinant of PD identified. These mutations are common in both early‐ and late‐onset PD, occurring in familial and idiopathic PD patients with a variable frequency among ethnic backgrounds. LRRK2 is a large gene, with 51 exons, encoding a multidomain protein. The most frequent mutation described is p.G2019S (c.6055G>A). This mutation is located in the kinase domain of the protein and has been observed in familial and idiopathic PD cases. The second most frequent mutation is p.R1441C (c.4321C>T), which has been identified in several populations. Therefore, the positions c.4321 and c.6055 in LRRK2 seem to represent mutational hotspots, although their relative prevalence is determined by ethnicity. Data suggest that the high prevalence of these mutations is a consequence of both founder effect and recurrence. On the other hand, two common non‐synonymous variations within LRRK2 and specific to Asian populations, p.G2385R and p.R1628P, have been found to represent genetic risk factors for the disease. Mean age at PD onset for all LRRK2 mutation carriers is 58.1±14 years. There is no obvious male or female preponderance. Although the onset of LRRK2‐associated PD occurs at a slightly younger age than idiopathic PD, this lacks significant clinical relevance. Clinically affected and some unaffected LRRK2 mutation carriers show a neurochemical profile of dopaminergic dysfunction, as assessed by positron emission tomography (PET), indistinguishable from that of idiopathic PD.

Keywords: Parkinson disease, mutation, neurodegenerative, LRRK2, prevalence, Dardarin
Correspondence: Pablo Mir, Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología, Hospital Universitario Virgen del Rocío, Avda. Manuel Siurot s/n, 41013 Sevilla, Spain. Tel: (+34)‐955012593; Fax: (+34)‐955012597; e‐mail: pablo.mir.sspa@juntadeandalucia.es