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

Abstract

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

DARPP‐32 cells and neuropil define striosomal system and isolated matrix cells in human striatum

“…For the human striatum, there are other neurochemicals that have been shown to favor either the striosome or matrix compartment such as acetylcholinesterase (Graybiel & Ragsdale, 1978), enkephalin (Emson, Arregui, Clement‐Jones, Sandberg, & Rossor, 1980), and calbindin (Ferrante et al., 1991; Holt et al., 1997). There appears to be limited mention in the literature of the compartmental organization of DARPP‐32‐positive cells into a specific striosomal/matrix pattern in the striatum of adult humans (Khan et al., 2021). DARPP‐32 is a protein that relies heavily on dopamine for its functions as a phosphatase and kinase inhibitor.…”

“…In the present study, it appears that the staining pattern of the human is different to that in the rat, as our studies in the rat show no marked presence or notable striosome enhancement of DARPP‐32 expression in striosomes in the rat striatum. This distribution of DARPP‐32 within the striosomes and matrix appears to be a distinguishing feature unique to the mature human striatum (Khan et al., 2021).…”

“…In the present study, it appears that the staining pattern of the human is different to that in the rat, as our studies in the rat show no marked presence or notable striosome enhancement of DARPP-32 expression in striosomes in the rat striatum. This distribution of DARPP-32 within the striosomes and matrix appears to be a distinguishing feature unique to the mature human striatum (Khan et al, 2021). Moreover, while some previously investigated neurochemicals tend to identify either the striosome (dopamine receptor D1) or matrix (calbindin) compartments consistently across the rodent and human striatum (Besson, Graybiel, & Nastuk, 1988;Crittenden & Graybiel, 2011;Gerfen et al, 1985;Holt et al, 1997;Liu & Graybiel, 1992;Murrin & Zeng, 1989), there appears to be conflicting evidence and conclusions regarding the distribution of TH within the rodent and human striatum.…”

“…There appears to be limited mention in the literature of the compartmental organization of DARPP-32-positive cells into a specific striosomal/matrix pattern in the striatum of adult humans (Khan et al, 2021). DARPP-32 is a protein that relies heavily on dopamine for its functions as a phosphatase and kinase inhibitor.…”

Homozygous Missense Variant in the N-Terminal Region of ANK3 Gene Is Associated with Developmental Delay, Seizures, Speech Abnormality, and Aggressive Behavior

“…Similarly, the prevalence of epilepsy with ID is 22.2% [Robertson et al, 2015;Nøstvik et al, 2021]. Genomic data analysis has shown the clustering of genes in various mental and neurodevelopmental disorders [Moreno-De-Luca et al, 2013;Khan et al, 2022]. The Association of ANK3 mutations with ASD, schizophrenia, ID, and bipolar disorder is additional evidence to this theme.…”