Mutation detection in the aspartoacylase gene in 17 patients with Canavan disease: four new mutations in the non-Jewish population

Sistermans, Erik A.; Coo, I.F.M. de; Beerendonk, H.M. van; Poll-Thé, Bwee Tien; Kleijer, Wim J.; Oost, B.A. van

doi:10.1038/sj.ejhg.5200477

Cited by 39 publications

(23 citation statements)

References 5 publications

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“…This is in contrast to a previous suggestion that active site mutations result in a severe phenotype (Surendran et al 2003b). The most common mutation among non-Ashkenazi Europeans, A305E (noncatalytic), has been implicated in severe, classical, and mild CD cases (Janson et al 2006,Shaag et al 1995,Sistermans et al 2000,Yalcinkaya et al 2005. Similarly, the most common mutation among Ashkenazim, E285A (catalytic), has also been implicated in multiple CD clinical courses (Shaag et al 1995).…”

Section: Discussionmentioning

confidence: 82%

“…Notably, missense mutations at His21, Glu24, Asp68, and Arg71 have been detected in CD patients (Sistermans et al 2000,Zeng et al 2002,Janson et al 2006. Although there are no CD mutations at Glu178, nearby CD mutations have been found at Pro181, Pro183, and Val186 (Sistermans et al 2000,Zeng et al 2002,Elpeleg & Shaag 1999, which suggests that Glu178 is an important catalytic residue.…”

Section: Introductionmentioning

confidence: 99%

“…Among Ashkenazi Jews, the E285A mutation is the most common (Elpeleg et al 1994,Feigenbaum et al 2004,Kaul et al 1994,Kaul et al 1996,Kronn et al 1995, and the A305E mutation is the most common one among other populations (Elpeleg & Shaag 1999,Janson et al 2006,Kaul et al 1994,Kaul et al 1996,Shaag et al 1995,Sistermans et al 2000,Yalcinkaya et al 2005,Zeng et al 2002. Less than half of the missense mutations in the ASPA gene have been shown to yield negligible ASPA activity compared with wild-type (WT) enzyme upon transient transfection into COS cells.…”

Section: Introductionmentioning

confidence: 99%

“…These include residues that are equivalent to those involved in zinc coordination (His21, Glu24, His116), shaping the substrate-binding cavity (Asp68), substrate binding (Arg71), transition state stabilization (Arg63), and catalysis (Glu178) (Makarova & Grishin 1999). Notably, missense mutations at His21, Glu24, Asp68, and Arg71 have been detected in CD patients (Sistermans et al 2000,Zeng et al 2002,Janson et al 2006. Although there are no CD mutations at Glu178, nearby CD mutations have been found at Pro181, Pro183, and Val186 (Sistermans et al 2000,Zeng et al 2002,Elpeleg & Shaag 1999, which suggests that Glu178 is an important catalytic residue.…”

Section: Introductionmentioning

confidence: 99%

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Mutational analysis of aspartoacylase: Implications for Canavan Disease

et al. 2007

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Mutations that result in undetectable activity of aspartoacylase, which catalyzes the deacetylation of N-acetyl-L-aspartate, correlate with Canavan Disease, a neurodegenerative disorder usually fatal during childhood. The underlying biochemical mechanisms of how these mutations ablate activity are poorly understood. Therefore, we developed and tested a three-dimensional homology model of aspartoacylase based on zinc dependent carboxypeptidase A. Mutations of the putative zinc-binding residues (H21G, E24D/G, and H116G), the general proton donor (E178A), and mutants designed to switch the order of the zinc-binding residues (H21E/E24H and E24H/H116E) yielded wild-type aspartoacylase protein levels and undetectable ASPA activity. Mutations that affect substrate carboxyl binding (R71N) and transition state stabilization (R63N) also yielded wild-type aspartoacylase protein levels and undetectable aspartoacylase activity. Alanine substitutions of Cys124 and Cys152, residues indicated by homology modeling to be in close proximity and in the proper orientation for disulfide bonding, yielded reduced ASPA protein and activity levels. Finally, expression of several previously tested (E24G, D68A, C152W, E214X, D249V, E285A, and A305E) and untested (H21P, A57T, I143T, P183H, M195R, K213E/G274R, G274R, and F295S) Canavan Disease mutations resulted in undetectable enzyme activity, and only E285A and P183H showed wild-type aspartoacylase protein levels. These results show that aspartoacylase is a member of the caboxypeptidase A family and offer novel explanations for most loss-of-function aspartoacylase mutations associated with Canavan Disease.

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Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mutational analysis of aspartoacylase: Implications for Canavan Disease

et al. 2007

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“…A nonsense mutation was found in 13.4% of the alleles from Jewish patients at codon 231, which converts tyrosine to a stop codon. The incidence of mutations in the ASPA gene are far less common in non-Jewish patients, and the mutations are distinct, and more diverse (Kaul et al, 1996;Sistermans et al, 2000). The most prevalent non-Jewish mutation was identified in codon 305, a missense mutation substituting alanine for glutamic acid.…”

Section: Naa and Canavan Diseasementioning

confidence: 99%

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Moffett

Ross

Arun

et al. 2007

Progress in Neurobiology

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1,126

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The brain is unique among organs in many respects, including its mechanisms of lipid synthesis and energy production. The nervous system-specific metabolite N-acetylaspartate (NAA), which is synthesized from aspartate and acetyl-coenzyme A in neurons, appears to be a key link in these distinct biochemical features of CNS metabolism. During early postnatal CNS development, the expression of lipogenic enzymes in oligodendrocytes, including the NAA-degrading enzyme aspartoacylase (ASPA), is increased along with increased NAA production in neurons. NAA is transported from neurons to the cytoplasm of oligodendrocytes, where ASPA cleaves the acetate moiety for use in fatty acid and steroid synthesis. The fatty acids and steroids produced then go on to be used as building blocks for myelin lipid synthesis. Mutations in the gene for ASPA result in the fatal leukodystrophy Canavan disease, for which there is currently no effective treatment. Once postnatal myelination is completed, NAA may continue to be involved in myelin lipid turnover in adults, but it also appears to adopt other roles, including a bioenergetic role in neuronal mitochondria. NAA and ATP metabolism appear to be linked indirectly, whereby acetylation of aspartate may facilitate its removal from neuronal mitochondria, thus favoring conversion of glutamate to alpha ketoglutarate which can enter the tricarboxylic acid cycle for energy production. In its role as a mechanism for enhancing mitochondrial energy production from glutamate, NAA is in a key position to act as a magnetic resonance spectroscopy marker for neuronal health, viability and number. Evidence suggests that NAA is a direct precursor for the enzymatic synthesis of the neuron specific dipeptide N-acetylaspartylglutamate, the most concentrated neuropeptide in the human brain. Other proposed roles for NAA include neuronal osmoregulation and axon-glial signaling. We propose that NAA may also be involved in brain nitrogen balance. Further research will be required to more fully understand the biochemical functions served by NAA in CNS development and activity, and additional functions are likely to be discovered.

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Genetic disorders affecting white matter in the pediatric age

Rocco

Biancheri

Rossi

et al. 2004

American J of Med Genetics Pt B

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Pediatric white matter disorders can be distinguished into well-defined leukoencephalopathies, and undefined leukoencephalopathies. The first category may be subdivided into: (a) hypomyelinating disorders; (b) dysmyelinating disorders; (c) leukodystrophies; (d) disorders related to cystic degeneration of myelin; and (e) disorders secondary to axonal damage. The second category, representing up to 50% of leukoencephalopathies in childhood, requires a multidisciplinar approach in order to define novel homogeneous subgroups of patients, possibly representing "new genetic disorders" (such as megalencephalic leukoencepahlopathy with subcortical cysts and vanishing white matter disease that have recently been identified). In the majority of cases, pediatric white matter disorders are inherited diseases. An integrated description of the clinical, neuroimaging and pathophysiological features is crucial for categorizing myelin disorders and better understanding their genetic basis. A review of the genetic disorders affecting white matter in the pediatric age, including some novel entities, is provided.

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Mutation detection in the aspartoacylase gene in 17 patients with Canavan disease: four new mutations in the non-Jewish population

Cited by 39 publications

References 5 publications

Mutational analysis of aspartoacylase: Implications for Canavan Disease

Mutational analysis of aspartoacylase: Implications for Canavan Disease

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Genetic disorders affecting white matter in the pediatric age

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