Confirmation of RAB32 Ser71Arg Involvement in Parkinson's Disease

Abstract

More than a dozen genes are involved in monogenic forms of Parkinson's disease (PD).¹ Their discovery have contributed to our understanding of the biology of PD and highlighted the role of α-synuclein, mitochondrial homeostasis, vesicle trafficking, endolysosomal system, and other pathways in PD.² However, they explain only less than 10% of PD cases, suggesting that more genes are still to be identified.

In an attempt to decipher the involvement of RAB proteins in PD, Gustavsson et al.³ have first identified that the RAB32 c.213C>G p.Ser71Arg variant cosegregates with the disease in three families and further reported an additional 13 unrelated heterozygous probands. The penetrance was incomplete. They show that RAB32 Arg71 does not affect the robust interaction between RAB32 and LRRK2 (a protein in which gain-of-function variants such as G2019S are well-known to contribute to PD), and that RAB32 Arg71 enhances LRRK2 kinase activation, reinforcing the pathogenicity likeliness. Another recent manuscript independently reported 18 new individuals with the RAB32 p.Ser71Arg in exome sequencing data of 2184 index familial PD cases (0.7%), whereas they observed a frequency of only 0.004% in control subjects, generating an odds ratio of 65.5.⁴ The phenotype was similar to typical PD, except for an earlier mean age at onset than usually reported (56 years old). No atypical sign was reported. Interestingly, both articles demonstrated that nearly all carriers (n = 31 and n = 34) shared a ~300-kb haplotype despite their disparate geographical origin (Tunisia, Canada, Italy, UK, etc.), suggesting a common ancestor.

We attempted to replicate this finding in our own dataset described elsewhere.⁵ Among 1292 PD index cases who underwent whole-exome sequencing, we identified one patient with the RAB32 p.Ser71Arg. Both parents of the proband were French. PD was diagnosed in her father at 71 years old, and he died at the age of 86. We were not able to perform a segregation analysis (Fig. 1). Her paternal uncle died at 35 years old from a cirrhosis, and at last examination neither of her two sisters had neurological symptoms. She presented at age 67 with asymmetrical gait disturbances before rapidly developing akinesia, rigidity, and resting tremor. Hyposmia appeared in the 2 years after the diagnosis. By age 70, her International Parkinson and Movement Disorder Society–sponsored revision of the Unified Parkinson's Disease Rating Scale Part III on score was 27, and her Hoehn and Yahr stage was at 3. She had no cognitive impairment, no oculomotor abnormalities, no sleep disorder, and no hallucination but developed urinary disturbances and postural instability with short and shuffling steps and falls. Cerebral magnetic resonance imaging was normal, and she was treated with levodopa (l-dopa) at 400 mg/day with a moderate response subjectively assessed by the neurologist and her at 30% to 40%. She developed dyskinesias 4 years after the disease onset following an increase of l-dopa. Dyskinesias remained present at last examination at age 74, when l-dopa levels were at 550 mg/day. Haplotype analysis performed by Single Nucleotide Polymorphism (SNP) array with additional imputation indicated that she shared the common 300-kb haplotype (Supporting Information Data S1 and Table S1).

We confirm the widespread distribution of the RAB32 p.Ser71Arg now detected in France. The frequency of the pathogenic variant in European individuals from our cohort of PD index cases is 0.1%. However, it represents 0.7% of European cases with a family history compatible with autosomal dominant inheritance. This finding is in the range of previously reported cohorts of index cases from PD families, ranging from 0.7%⁴ to 2.3%.³ Similar to patients reported to date, the phenotype is that of typical PD. However, the l-dopa response was not as good as previously reported. Thus, because RAB32 p.Ser71Arg appears to be not clinically recognizable, its inclusion in the diagnostic strategy of clinical laboratories seems necessary for its identification and ultimately for providing genetic counseling to patients with PD.

(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.

G.C.: 1C, 2A, 2B, 2C, 3A, 3B.

C.T.: 1A, 1B, 1C, 2A, 2B, 3B.

C.B-C.: 1C, 2C, 3B.

A.L.: 2B, 2C, 3B.

G.C.K..: 2B, 2C, 3B.

L.W.: 1C, 2B.

F.C.: 1C, 2B, 3B.

S.L.: 1A, 1B, 1C, 2A, 2B, 2C, 3B.

A.B: 1A, 1B, 1C, 2A, 2B, 2C, 3B.

G.C. is supported by the Global Parkinson's Genetics Program (GP2). GP2 is funded by the Aligning Science Across Parkinson's (ASAP) initiative and implemented by The Michael J. Fox Foundation for Parkinson's Research (https://gp2.org). For a complete list of GP2 members see https://gp2.org. S.L. has received grants from Fondation de la Recherche Médicale (FRM, MND202004011718).