A Novel Homozygous p.L539F Mutation Identified in PINK1 Gene in a Moroccan Patient with Parkinsonism

Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease. Ten of fifteen causative genes linked to familial forms of PD have been reported to cause autosomal recessive forms. Among them, mutations in the PTEN-induced kinase 1 (PINK1) gene were shown to be responsible for a phenotype characterized by early onset, good response to levodopa, and a benign course. Using chromosomal microarray analysis and Sanger sequencing, we identified a homozygous G/C substitution in a 58-year-old Moroccan man diagnosed with recessive inherited Parkinson’s disease. This G-to-C transition occurred at position 1617 leading to an amino acid change L/F at position 539 located in highly conserved motif in the C terminal sequence of PINK1. Interestingly, the c.1617G>C substitution is absent in 192 ethnically matched control chromosomes. Our findings have shown that the p.L539F is a novel mutation located in the C terminal sequence of the PINK1 protein that could be pathogenic and responsible for a clinical phenotype resembling idiopathic Parkinson’s disease with rapid progression and early cognitive impairment

Evidence for prehistoric origins of the G2019S mutation in the North African Berber population.

The most common cause of the monogenic form of Parkinson's disease known so far is the G2019S mutation of the leucine-rich repeat kinase 2 (LRRK2) gene. Its frequency varies greatly among ethnic groups and geographic regions ranging from less than 0.1% in Asia to 40% in North Africa. This mutation has three distinct haplotypes; haplotype 1 being the oldest and most common. Recent studies have dated haplotype 1 of the G2019S mutation to about 4000 years ago, but it remains controversial whether the mutation has a Near-Eastern or Moroccan-Berber ancestral origin. To decipher this evolutionary history, we genotyped 10 microsatellite markers spanning a region of 11.27 Mb in a total of 57 unrelated Moroccan PD patients carrying the G2019S mutation for which the Berber or Arab origin was established over 3 generations based on spoken language. We estimated the age of the most recent common ancestor for the 36 Arab-speaking and the 15 Berber-speaking G2019S carriers using the likelihood-based method with a mutation rate of 10-4. Data analysis suggests that the shortest haplotype originated in a patient of Berber ethnicity. The common founder was estimated to have lived 159 generations ago (95% CI 116-224) for Arab patients, and 200 generations ago (95% CI 123-348) for Berber patients. Then, 29 native North African males carrying the mutation were assessed for specific uniparental markers by sequencing the Y-chromosome (E-M81, E-M78, and M-267) and mitochondrial DNA (mtDNA) hypervariable regions (HV1 and HV2) to examine paternal and maternal contributions, respectively. Results showed that the autochthonous genetic component reached 76% for mtDNA (Eurasian and north African haplogroups) and 59% for the Y-chromosome (E-M81 and E-M78), suggesting that the G2019S mutation may have arisen in an autochthonous DNA pool. Therefore, we conclude that LRRK2 G2019S mutation most likely originated in a Berber founder who lived at least 5000 years ago (95% CI 3075-8700)

LRRK2 G2019S Mutation: Prevalence and Clinical Features in Moroccans with Parkinson’s Disease

Background. The LRRK2 G2019S mutation is the most common genetic determinant of Parkinson’s disease (PD) identified to date. This mutation, reported in both familial and sporadic PD, occurs at elevated frequencies in Maghreb population. In the present study, we examined the prevalence of the G2019S mutation in the Moroccan population and we compared the motor and nonmotor phenotype of G2019S carriers to patients with idiopathic Parkinson’s disease. Methods. 100 PD patients were assessed for motor and nonmotor symptoms, current medication, and motor complication including motor fluctuations and dyskinesia. The LRRK2 G2019S mutation was investigated by direct sequencing in patients and ethnically matched controls, all of Moroccan origin. Results. Among the 100 PD Moroccan patients, 41 (41%) were carriers of the G2019S mutation. The mutation frequency was higher among probands with autosomal dominant inheritance (76%) than among sporadic ones (28%). Interestingly, G2019S mutation was also found in 5% of control individuals. Clinically, patients carrying the G2019S mutation have more dystonia (OR = 4.6, p = 0.042) and more sleep disorders (OR = 2.4, p = 0.045) than noncarriers. Conclusions. The LRRK2 G2019S prevalence in Morocco is the highest in the world reported to date. Some clinical features in G2019S carriers such as dystonia and sleep disturbances are worth noting

Mutation Analysis of Consanguineous Moroccan Patients with Parkinson’s Disease Combining Microarray and Gene Panel

During the last two decades, 15 different genes have been reported to be responsible for the monogenic form of Parkinson’s disease (PD), representing a worldwide frequency of 5–10%. Among them, 10 genes have been associated with autosomal recessive PD, with PRKN and PINK1 being the most frequent. In a cohort of 145 unrelated Moroccan PD patients enrolled since 2013, 19 patients were born from a consanguineous marriage, of which 15 were isolated cases and 4 familial. One patient was homozygous for the common LRRK2 G2019S mutation and the 18 others who did not carry this mutation were screened for exon rearrangements in the PRKN gene using Affymetrix Cytoscan HD microarray. Two patients were determined homozygous for PRKN exon-deletions, while another patient presented with compound heterozygous inheritance (3/18, 17%). Two other patients showed a region of homozygosity covering the 1p36.12 locus and were sequenced for the candidate PINK1 gene, which revealed two homozygous point mutations: the known Q456X mutation in exon 7 and a novel L539F variation in exon 8. The 13 remaining patients were subjected to next-generation sequencing (NGS) that targeted a panel of 22 PD-causing genes and overlapping phenotypes. NGS data showed that two unrelated consanguineous patients with juvenile-onset PD (12 and 13 years) carried the same homozygous stop mutation W258X in the ATP13A2 gene, possibly resulting from a founder effect; and one patient with late onset (76 years) carried a novel heterozygous frameshift mutation in SYNJ1. Clinical analysis showed that patients with the ATP13A2 mutation developed juvenile-onset PD with a severe phenotype, whereas patients having either PRKN or PINK1 mutations displayed early-onset PD with a relatively mild phenotype. By identifying pathogenic mutations in 45% (8/18) of our consanguineous Moroccan PD series, we demonstrate that the combination of chromosomal microarray analysis and NGS is a powerful approach to pinpoint the genetic bases of autosomal recessive PD, particularly in countries with a high rate of consanguinity

Age estimation of the G2019S mutation using an intergenerational time interval of 25 years.

<p>Age estimation of the G2019S mutation using an intergenerational time interval of 25 years.</p

Shared haplotype inferred from five G2019S homozygous patients.

<p>Shared haplotype inferred from five G2019S homozygous patients.</p

Map of the Mediterranean Basin illustrating the distribution of the G2019S mutation frequencies and the main conquests and invasions that the Maghreb has experienced since antiquity.

<p>Map of the Mediterranean Basin illustrating the distribution of the G2019S mutation frequencies and the main conquests and invasions that the Maghreb has experienced since antiquity.</p

mtDNA and Y-chomosomeuniparental markers analysis for the 29 G2019S male carriers.

<p>mtDNA and Y-chomosomeuniparental markers analysis for the 29 G2019S male carriers.</p