Identification of Ser71Arg mutation in RAB32 gene in familial Parkinson's disease from Southern Italy

Abstract

We identified the RAB32 c.213 C > G variant in 7/300 unrelated familial PD patients (not found in 300 controls) from Southern Italy, screened by Sanger sequencing. We found a prevalence of 2.33%, higher than that observed in recent international studies (0.0-0.7%), supporting RAB32 gene as a notable cause of familial PD in the Mediterranean area. We first report prodromal PD signs in unaffected mutated family members, suggesting long-term follow-up in RAB32 carriers.

Fig. 1. The figure shows the Sanger Sequencing results.

A reference electropherogram showing the wildtype C at 213 position (at the top of the figure) and the electropherograms showing 213 C > G substitution in the 7 PD patients carrying the c.213 C > G (p.Ser71Arg) RAB32 variant. The gray box at the bottom of the figure shows protein alignment of RAB32 demonstrating a strong conservation of Arginine 71.

Fig. 2. The pedigrees of two probands (PD_001 and PD_002) are shown in the figure.

On the left, PD_001 is the 75-year-old gentleman pointed out by the black arrow; his paternal uncle had PD; one of his sisters (III-02) and his brother (III-07) carried the c.213 C > G (p.Ser71Arg) RAB32 variant, but had no clinical signs of PD and no suspicion of RBD; both of them however showed enhanced blink reflex recovery cycle at ISI: 200 ms, reflecting brainstem excitability, and the brother (III-007) had olfactory loss, with smell test in the hyposmia range. On the right, PD_002 is the 79-year-old lady pointed out by the black arrow; her maternal grandmother had PD; her non-consanguineous husband was affected by sporadic late onset PD (onset at 70 years old) with no mutations in known PD gene (including RAB32). Her two sons had signs suggestive of prodromal PD: IV-01 had olfactory loss, with smell test in the hyposmia range; IV-02 had strong clinical suspicion of RBD and showed enhanced blink reflex recovery cycle at ISIs of 100 and 200 msec, reflecting brainstem excitability. PD Parkinson’s disease, M presence of c.213 C > G (p.Ser71Arg) RAB32 variant in heterozygosis, wt wildtype RAB32 gene, RBD REM Behavior disorder. For PD patients, age at examination is shown on the left and age at PD onset is shown on the right; for all other tested individuals, age at examination is shown.