Novel mutations, pseudo‐dominant inheritance, and possible familial affects in patients with autosomal recessive juvenile parkinsonism

Maruyama, Mieko; Ikeuchi, Takeshi; Saito, Masaaki; Ishikawa, Atsushi; Yuasa, Tatsuhiko; Tanaka, Hajime; Hayashi, Shigenari; Wakabayashi, Koichi; Takahashi, Hitomi; Tsuji, Shoji

doi:10.1002/1531-8249(200008)48:2<245::aid-ana15>3.3.co;2-u

Cited by 18 publications

(32 citation statements)

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“…Thus in the first reaction (transthiolation), the C-terminus of ubiquitin is transferred from an E2 enzyme’s cysteine to the acceptor cysteine, resulting in the formation of a thioester intermediate (Figure 1). In Parkin, the acceptor cysteine Cys431 is required for its ubiquitin ligase activity (Zhang et al, 2000; Wenzel et al, 2011) and the mutation C431F causes PD (Maruyama et al, 2000), in agreement with its proposed role in catalysis. The second step of the reaction (acyl transfer) involves the transfer of ubiquitin C-terminus from the acceptor cysteine to an amino group on a substrate, forming an isopeptide bond.…”

Section: Parkinmentioning

confidence: 85%

Structure and Function of Parkin, PINK1, and DJ-1, the Three Musketeers of Neuroprotection

Trempe¹,

Fon²

2013

Front. Neurol.

119

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Autosomal recessive forms of Parkinson’s disease are caused by mutations in three genes: Parkin, PINK1, and DJ-1. These genes encode for proteins with distinct enzymatic activities that may work together to confer neuroprotection. Parkin is an E3 ubiquitin ligase that has been shown to ubiquitinate substrates and to trigger proteasome-dependent degradation or autophagy, two crucial homeostatic processes in neurons. PINK1 is a mitochondrial protein kinase whose activity is required for Parkin-dependent mitophagy, a process that has been linked to neurodegeneration. Finally, DJ-1 is a protein homologous to a broad class of bacterial enzymes that may function as a sensor and modulator of reactive oxygen species, which have been implicated in neurodegenerative diseases. Here, we review the literature on the structure and biochemical functions of these three proteins.

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Section: Parkinmentioning

confidence: 85%

Structure and Function of Parkin, PINK1, and DJ-1, the Three Musketeers of Neuroprotection

Trempe¹,

Fon²

2013

Front. Neurol.

119

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“…Missense mutations affecting conserved cysteine in the RING domain of Parkin have been found in patients with inherited Parkinson disease. 27 Remarkably, a subgroup of patients with mutations in LRSAM1 have developed phenotypes of Parkinson disease. 28 In summary, we have identified a novel missense mutation that alters cysteine to arginine in the RING domain of LRSAM1.…”

Section: Discussionmentioning

confidence: 99%

A novel missense mutation of CMT2P alters transcription machinery

Arpag

Züchner

et al. 2016

Annals of Neurology

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Objective Charcot-Marie-Tooth type 2P (CMT2P) has been associated with frame-shift mutations in the RING domain of LRSAM1 (an E3 ligase). This study describes families with a novel missense mutation of LRSAM1 gene and explores pathogenic mechanisms of CMT2P. Methods Patients with CMT2P were characterized clinically, electrophysiologically and genetically. A neuronal model with the LRSAM1 mutation was created using CRISPR/Cas9 technology. The neuronal cell-line along with fibroblasts isolated from the patients was used to study RNA-binding proteins. Results This American family with dominantly inherited axonal polyneuropathy reveals a phenotype similar to those in previously reported non-US families. The affected members in our family co-segregated with a novel missense mutation Cys694Arg that alters a highly conserved cysteine in the RING domain. This mutation leads to axonal degeneration in the in vitro neuronal cell-line. Moreover, using protein mass spectrometry, we identified a group of RNA binding proteins (including FUS, a protein critically involved in motor neuron degeneration) that interacted with LRSAM1. The interactions were disrupted by the Cys694Arg mutation, which resulted in reduction of intranuclear RNA-binding proteins. Interpretation Our findings suggest that the mutant LRSAM1 may aberrantly affect the formation of transcription machinery. Given a similar mechanism has been reported in motor neuron degeneration of amyotrophic lateral sclerosis, abnormalities of RNA/RNA-binding protein complex may play a role in the neuronal degeneration of CMT2P.

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“…To date, 79 different parkin mutations have been described: 45 point mutations including 20 truncating, 22 missense, and 3 splice mutations, as well as 34 exon rearrangements including 24 deletions and 10 multiplications. 4,14,15,21,[25][26][27][32][33][34][35]37,41,[47][48][49][50][51][52][53][54][55][56][57][58] The large spectrum of parkin gene defects, which differ in their predicted consequences on the function of the protein, raises the question of their role in the variabil- ity of the phenotype. We indeed have found some differences.…”

Section: Discussionmentioning

confidence: 99%

“…[32][33][34] This differs from the pseudodominant inheritance described in rare families in which all patients carry two mutations. [35][36][37] The aim of our study was to compare large series of patients with and without parkin mutations and to assess the influence of the number and the nature of the mutations on the phenotype of the patients.…”

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confidence: 99%

How much phenotypic variation can be attributed to parkin genotype?

Lohmann

Periquet

Bonifati

et al. 2003

Annals of Neurology

283

211

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To establish phenotype-genotype correlations in early-onset parkinsonism, we have compared the phenotype of a large series of 146 patients with and 250 patients without parkin mutations. Although no single sign distinguished the groups, patients with mutations had significantly earlier and more symmetrical onset, dystonia more often at onset and hyperreflexia, slower progression of the disease, and a tendency toward a greater response to levodopa despite lower doses. After forward stepwise multiple logistic regression analysis, dystonia at onset and brisk reflexes were not longer significantly different but were correlated with age at onset rather than the presence of the parkin mutation. Age at onset in carriers of parkin mutations varied as did the rate of progression of the disease: the younger the age at onset the slower the evolution. The genotype influenced the phenotype: carriers of at least one missense mutation had a higher United Parkinson's Disease Rating Scale motor score than those carrying two truncating mutations. The localization of the mutations was also important because missense mutations in functional domains of parkin resulted in earlier onset. Patients with a single heterozygous mutation had significantly later and more asymmetrical onset and more frequent levodopa-induced fluctuations and dystonia than patients with two mutations.

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Novel mutations, pseudo‐dominant inheritance, and possible familial affects in patients with autosomal recessive juvenile parkinsonism

Cited by 18 publications

References 0 publications

Structure and Function of Parkin, PINK1, and DJ-1, the Three Musketeers of Neuroprotection

Structure and Function of Parkin, PINK1, and DJ-1, the Three Musketeers of Neuroprotection

A novel missense mutation of CMT2P alters transcription machinery

How much phenotypic variation can be attributed to parkin genotype?

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