A Homozygous Missense Variant in PPP1R1B/DARPP‐32 Is Associated With Generalized Complex Dystonia

Amjad Khan (1, 2, 3, 4, 5) , Anne Molitor (1, 2, 3, 4, 5) , Sylvain Mayeur (1, 2, 3, 4, 5, 6) , Gaoqun Zhang (7) , Bruno Rinaldi (8) , Béatrice Lannes (5, 6) , Benoît Lhermitte (5, 6) , Muhammad Umair (9, 10) , Stefan T. Arold (11, 12) , Sylvie Friant (8) , Sepand Rastegar (7) , Mathieu Anheim (5, 13, 6) , Seiamak Bahram (1, 5, 14, 2, 3, 4, 15) , Raphaël Carapito (1, 5, 14, 2, 3, 4, 15)

1 IRM - Immuno-Rhumatologie Moléculaire
2 GENOMAX [plateforme]
3 OMICARE - Fédération Hospitalo-Universitaire
4 Laboratoire d'excellence (Labex) Transplantex (Nouveaux loci d’histocompatibilité et biomarqueurs en transplantation humaine, de la découverte à l’application clinique)
5 FMTS - Fédération de Médecine Translationnelle de Strasbourg
6 CHU Strasbourg - Centre Hospitalier Universitaire [Strasbourg]
7 KIT - Karlsruher Institut für Technologie
8 GMGM - Génétique moléculaire, génomique, microbiologie
9 KSAU-HS - King Saud Bin Abdulaziz University for Health Sciences [Riyadh]
10 Centurion University of Technology and Management [India]
11 KAUST - King Abdullah University of Science and Technology [Saudi Arabia]
12 CBS - Centre de Biologie Structurale [Montpellier]
13 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
14 Nouvel Hôpital Civil de Strasbourg
15 HUS - Les Hôpitaux Universitaires de Strasbourg

Background: The dystonias are a heterogeneous group of hyperkinetic disorders characterized by sustained or intermittent muscle contractions that cause abnormal movements and/or postures. Although more than 200 causal genes are known, many cases of primary dystonia have no clear genetic cause. Objectives: To identify the causal gene in a consanguineous family with three siblings affected by a complex persistent generalized dystonia, generalized epilepsy, and mild intellectual disability. Methods: We performed exome sequencing in the parents and two affected siblings and characterized the expression of the identified gene by immunohistochemistry in control human and zebrafish brains. Results: We identified a novel missense variant (c.142G>A (NM_032192); p.Glu48Lys) in the protein phosphatase 1 regulatory inhibitor subunit 1B gene (PPP1R1B) that was homozygous in all three siblings and heterozygous in the parents. This gene is also known as dopamine and cAMP-regulated neuronal phosphoprotein 32 (DARPP-32) and has been involved in the pathophysiology of abnormal movements. The uncovered variant is absent in public databases and modifies the conserved glutamate 48 localized close to the serine 45 phosphorylation site. The PPP1R1B protein was shown to be expressed in cells and regions involved in movement control, including projection neurons of the caudate-putamen, substantia nigra neuropil, and cerebellar Purkinje cells. The latter cells were also confirmed to be positive for PPP1R1B expression in the zebrafish brain. Conclusions: We report the association of a PPP1R1B/DARPP-32 variant with generalized dystonia in man. It might be relevant to include the sequencing of this new gene in the diagnosis of patients with otherwise unexplained movement disorders. © 2021 International Parkinson and Movement Disorder Society.

Mots clés: autosomal recessive generalized dystonia; exome sequencing; PPP1R1B; DARPP-32

Domaines: Médecine humaine et pathologie; Génétique humaine

Amjad Khan, Anne Molitor, Sylvain Mayeur, Gaoqun Zhang, Bruno Rinaldi, et al.. A Homozygous Missense Variant in PPP1R1B/DARPP‐32 Is Associated With Generalized Complex Dystonia. Movement Disorders, 2022, 37 (2), pp.365-374. ⟨10.1002/mds.28861⟩. ⟨hal-03509022⟩