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Neonatal adrenoleukodystrophy/disorders of peroxisomal biogenesis
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The PEX1 gene codes for a member of the AAA protein family of ATPases, which interacts with another ATPase coded for by PEX6, and this interaction is required for matrix protein import [61, 62]. The cDNA codes for a hydrophylic protein of 1283 amino acids [62]. Defects in the PEX1 gene account for over half of patients with defects of peroxisomal biogenesis [63, 64]. Some 90 different mutations in PEX1 have been described [65]. Two mutations, G843D [21] and 2097insT [66], are common, G843D is the most common, and the clinical effect is relatively mild [25]. PEX1 mutations lead to severe defects in matrix protein import and destabilization of PEX5, the receptor for the type 1 peroxisomal targeting signal [23]. Genotype tends to correlate with phenotype in the sense that missense mutations have been found in milder presentations and nonsense mutations, deletions, and insertions in severe disease [64]. Thus, the type of mutation can be helpful in prognosis. The G843D mutation not only leads to milder disease in the homozygote, but also appears to ameliorate the effects of genes that usually cause severe disease. It was found in homozygous fashion in at least one patient with neonatal ALD [23] and several with infantile Refsum disease. The mutation was found on one of two alleles in patients with Zellweger syndrome, as well as these two diseases [62]. A frameshift mutation in exon 18 was relatively common in Australasian patients [63]. In an assembly of 168 patients, p.G843D and c.9097 insT accounted for more than 80 percent of abnormal alleles. Class I mutations led to residual protein concentrations and function, and milder disease, while class II led to no or almost no PEX protein and a severe phenotype [67]. Mutations causing premature termination were widely distributed through the gene, while missense mutations were concentrated in the essential AAA domains of the PEX1 protein [68].
High diagnostic yield and novel variants in very late-onset spasticity
Published in Journal of Neurogenetics, 2019
Momen Almomen, Kristina Martens, Asfia Quadir, Carly Sabine Pontifex, Alexandra Hanson, Lawrence Korngut, Gerald Pfeffer
Hereditary spastic paraplegia (HSP) is a heterogeneous group of disorders that are characterised by degeneration of descending cortical spinal tracts, causing progressive spasticity starting in the legs, and often including bladder dysfunction (Harding, 1983). Some subtypes of HSP may have presentation in late adulthood, the most well-known of these being HSP type 4 (caused by dominant SPAST mutations, which encode the protein spastin) and HSP type 7 (caused by biallelic SPG7 mutations, which encode the protein paraplegin) (Chelban et al., 2017; Pfeffer et al., 2015). Both of these proteins are members of the AAA protein family (ATPase associated with a variety of cellular activities), although they have differing cellular localizations and functions: spastin is involved in microtubule metabolism in the cytoskeleton (Errico, Ballabio, & Rugarli, 2002), whereas paraplegin is localised to mitochondria where it appears to have an important effect on mitochondrial dynamics and maintenance, along with its binding partner AFG3L2 (Gorman et al., 2015; Pfeffer et al., 2014).
ATAD2 in cancer: a pharmacologically challenging but tractable target
Published in Expert Opinion on Therapeutic Targets, 2018
Muzammal Hussain, Yang Zhou, Yu Song, H.M. Adnan Hameed, Hao Jiang, Yaoquan Tu, Jiancun Zhang
ATAD2 protein is a member of the AAA ATPase family that is remarkably conserved from multicellular eukaryotes, including yeast, to humans [18]. The hallmark of AAA family of proteins is a structurally conserved ATPase domain that is responsible for ATP binding and hydrolysis [19,20]. The members of AAA family are involved in a remarkably diverse range of cellular processes, including cell cycle regulation, protein unfolding and degradation, organelle biogenesis and intracellular transport [20,21]. This functional diversity is attained through evolutionarily additions of structural motifs and modifications to the common core architecture of ATPase domain, also referred to as AAA module, which make the AAA proteins to undergo conformational changes in the context of their adapted mechanistic roles [19–22].
Genetics of frontotemporal dementia in China
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2021
Yaling Jiang, Bin Jiao, Xuewen Xiao, Lu Shen
The VCP protein is a member of the ATPases associated with a variety of cellular activities (AAA) protein superfamily and is a key regulator at the intersection of autophagy and the ubiquitin-proteasome system (77,78). Mutations in the VCP gene were identified in families with inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) (79). Most IBMPFD-associated mutations are located within the N-terminal CDC48 domain, which is involved in ubiquitin-binding, especially in exon5 (R155C, R155H, R155P, R155L, R155S, G157R, R159C, R159P, and R191Q) and exon3 (R93C, R95G, and G97E) (28,80–82).