On the Molecular Basis of D-Bifunctional Protein Deficiency Type III

Mehtälä, Maija L.; Lensink, Marc F.; Pietikäinen, Laura P.; Hiltunen, J. Kalervo; Glumoff, Tuomo

doi:10.1371/journal.pone.0053688

Cited by 8 publications

(5 citation statements)

References 42 publications

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“…Examples are N158D and E232K in multifunctional enzyme (MFE) type 2 involved in β-oxidation and causing D-bifunctional protein (D-BP) deficiency when altered. N158D variant decreases Vmax and kcat/K m ratio and increases both K m and k cat values (Mehtälä et al 2013). E232K alteration has quite normal K m value; however, the other kinetic characteristics are changed.…”

Section: Effect On Protein Activitymentioning

confidence: 87%

Types and effects of protein variations

Vihinen

2015

Hum Genet

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Types and effects of protein variations. Vihinen, MaunoPublished in: Human Genetics DOI: 10.1007/s00439-015-1529-6Published: 2015-01-01Link to publication Citation for published version (APA): Vihinen, M. (2015). Types and effects of protein variations. Human Genetics, 134(4), 405-421. DOI: 10.1007405-421. DOI: 10. /s00439-015-1529 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. for all variation types, a more detailed description can be made by explaining changes to protein function, structure and properties. Examples are provided for the effects and mechanisms, usually in relation to human diseases. In addition, the examples are selected so that protein 3D structural changes, when relevant, are included and visualized. Here, systematics is described for protein variants based on VariO. It will benefit the unequivocal description of variations and their effects and further reuse and integration of data from different sources. 1 TYPES AND EFFECTS OF PROTEIN VARIATIONS

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Section: Effect On Protein Activitymentioning

confidence: 87%

Types and effects of protein variations

Vihinen

2015

Hum Genet

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“…The side chain of Ala175 is situated on the outer surface of the dimerized α helix. 26 Unlike variants of cysteine or serine residues, mutation of a threonine residue results in an increased side chain volume and consequently altered packing that might affect the homodimer interaction ( figure 4C). Although the mutations do not directly affect residues in the active site, they potentially alter the stability of the dimer.…”

Section: Distribution and Quantification Of Hsd17b4 Proteins In The Pmentioning

confidence: 99%

Biallelic mutation of HSD17B4 induces middle age–onset spinocerebellar ataxia

et al. 2020

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ObjectiveTo determine the genetic underpinnings of slowly progressive spinocerebellar ataxia, autosomal recessive (SCAR), we performed exome analysis and examined the relationship between clinical severity and functional change induced by the mutation.MethodsHomozygosity fingerprinting and exome sequencing were performed to identify causative mutations in 2 consanguineous families. We assessed the expression of D-bifunctional protein (DBP) and the amount of dimerized DBP in fibroblasts by immunoblot and quantitative reverse transcription PCR. The pathogenicity of the mutation was evaluated using the Combined Annotation-Dependent Depletion (CADD) scores; these results were compared with the scores of previously reported mutations.ResultsWe identified a homozygous mutation as causative of middle age–onset SCAR: p.Ala175Thr, which is located in HSD17B4 that encodes peroxisomal DBP. The patients developed cerebellar ataxia, and the subsequent progression was slow. The symptoms presented were milder than those in previously reported cases. The messenger RNA expression levels were normal, but protein levels were diminished. Dimerization of DBP was also reduced. The CADD score of the identified mutation was lower than those of previously reported mutations.ConclusionsThis is the report of middle age–onset DBP deficiency. Residual functional DBP caused relatively mild symptoms in the affected patients, i.e., slowly progressive ataxia and hearing loss. This study broadens the scope of DBP deficiency phenotypes and indicates that CADD scores may be used to estimate the severity of DBP deficiencies.

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“…Moreover, several polymorphisms of MAP3K are associated with triglyceride levels, cancer, and neurodegenerative diseases . The protein encoded by HSD17B4 is a bifunctional enzyme (multifunctional enzyme type 2; MFE‐2) that participates in peroxisomal lipid metabolism . In this sense, peroxisomal oxidation of fatty acids produces oxidative stress, a process implicated in obesity.…”

Section: Genomics and Central Obesitymentioning

confidence: 99%

Single-nucleotide polymorphisms and DNA methylation markers associated with central obesity and regulation of body weight

et al. 2014

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Visceral fat is strongly associated with the development of specific obesity-related metabolic alterations. Genetic and epigenetic mechanisms seem to be involved in the development of obesity and visceral adiposity. The aims of this review are to identify the single-nucleotide polymorphisms related to central obesity and to summarize the main findings on DNA methylation and obesity. A search of the MEDLINE database was conducted to identify genome-wide association studies, meta-analyses of genome-wide association studies, and gene-diet interaction studies related to central obesity, and, in addition, studies that analyzed DNA methylation in relation to body weight regulation. A total of 8 genome-wide association studies and 9 meta-analyses of genome-wide association studies reported numerous single-nucleotide polymorphisms to be associated with central obesity. Ten studies analyzed gene-diet interactions and central obesity, while 2 epigenome-wide association studies analyzed DNA methylation patterns and obesity. Nine studies investigated the relationship between DNA methylation and weight loss, excess body weight, or adiposity outcomes. Given the development of new sequencing and omics technologies, significantly more knowledge on genomics and epigenomics of obesity and body fat distribution will emerge in the near future.

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On the Molecular Basis of D-Bifunctional Protein Deficiency Type III

Cited by 8 publications

References 42 publications

Types and effects of protein variations

Types and effects of protein variations

Biallelic mutation of HSD17B4 induces middle age–onset spinocerebellar ataxia

Single-nucleotide polymorphisms and DNA methylation markers associated with central obesity and regulation of body weight

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