Genotype-based databases for variants causing rare diseases

Lanthaler, Barbara; Wieser, Stefanie; Deutschmann, Andrea; Schossig, Anna; Fauth, Christine; Zschocke, Johannes; Witsch‐Baumgartner, Martina

doi:10.1016/j.gene.2014.08.016

Cited by 11 publications

(7 citation statements)

References 9 publications

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“…Missense mutations compose Ͼ85% of the known alleles, although the two most common are a splice acceptor site mutation (IVS8 -1GϾC) and a nonsense mutation (W151X) (37). As these would abolish DHCR7 expression, we selected the four most common missense mutations to study (T93M, V326L, R352W, and R352Q) (38). Despite equal transcript levels after transient expression in HEK-293 cells, protein expression was significantly reduced with all four mutations (Fig.…”

Section: Low Dhcr7 Expression In Slos Mutationsmentioning

confidence: 99%

Cholesterol-mediated Degradation of 7-Dehydrocholesterol Reductase Switches the Balance from Cholesterol to Vitamin D Synthesis

Prabhu

Luu

Sharpe

et al. 2016

Journal of Biological Chemistry

121

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Cholesterol is detrimental to human health in excess but is also essential for normal embryogenesis. Hence, enzymes involved in its synthesis possess many layers of regulation to achieve balanced cholesterol levels. 7-Dehydrocholesterol reductase (DHCR7) is the terminal enzyme of cholesterol synthesis in the Kandutsch-Russell pathway, converting 7-dehydrocholesterol (7DHC) to cholesterol. In the absence of functional DHCR7, accumulation of 7DHC and a lack of cholesterol production leads to the devastating developmental disorder, Smith-Lemli-Opitz syndrome. This study identifies that statin treatment can ameliorate the low DHCR7 expression seen with common Smith-Lemli-Opitz syndrome mutations. Furthermore, we show that wild-type DHCR7 is also relatively labile. In an example of end-product inhibition, cholesterol accelerates the proteasomal degradation of DHCR7, resulting in decreased protein levels and activity. The loss of enzymatic activity results in the accumulation of the substrate 7DHC, which leads to an increased production of vitamin D. Thus, these findings highlight DHCR7 as an important regulatory switch between cholesterol and vitamin D synthesis.

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Section: Low Dhcr7 Expression In Slos Mutationsmentioning

confidence: 99%

Cholesterol-mediated Degradation of 7-Dehydrocholesterol Reductase Switches the Balance from Cholesterol to Vitamin D Synthesis

Prabhu

Luu

Sharpe

et al. 2016

Journal of Biological Chemistry

121

View full text Add to dashboard Cite

show abstract

“…Since the early discoveries of genes such as CFTR , DMD , FMR1 , and PAH , there have been various efforts to create gene‐/disease‐specific mutation databases. These efforts started with locus‐specific databases (LSDBs) [Fokkema et al., , ; Pan et al., ; Bean et al., ; International Alport Mutation et al., ; Lanthaler et al., ] made by individual research groups for genes such as TP53 [Forbes et al., ]. In the last decade as sequencing costs dropped, new genes were rapidly discovered.…”

Section: Variant Databasesmentioning

confidence: 99%

“…This has implications in all areas of medicine and is not limited to rare diseases [Macarthur, ]. Data from large‐scale sequencing projects, such as the 1000 Genomes Project and projects focused on data aggregation, such as the ExAC database, are now freely available for use in research and diagnostic settings [Watt et al., ; Lanthaler et al., ]. These projects have made two things clear: (1) certain regions of the human genome still cannot be sequenced with adequate depth or simply have not been assigned a sequence based on their content, strand orientation, or errors in assembly; and (2) there are thousands of rare variants in the general population that are difficult to classify.…”

Section: The Burden Of Data From Large‐scale Sequencing Projectsmentioning

confidence: 99%

Gene Variant Databases and Sharing: Creating a Global Genomic Variant Database for Personalized Medicine

Bean

Hegde

2016

Human Mutation

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Revolutionary changes in sequencing technology and the desire to develop therapeutics for rare diseases have led to the generation of an enormous amount of genomic data in the last five years. Large-scale sequencing done in both research and diagnostic laboratories has linked many new genes to rare diseases, but has also generated a number of variants that we cannot interpret today. It is clear that we remain a long way from a complete understanding of the genomic variation in the human genome and its association with human health and disease. Recent studies identified susceptibility markers to infectious diseases and also the contribution of rare variants to complex diseases in different populations. The sequencing revolution has also led to the creation of a large number of databases that act as “keepers” of data, and in many cases give an interpretation of the effect of the variant. This interpretation is based on reports in the literature, prediction models, and in some cases is accompanied by functional evidence. As we move towards the practice of genomic medicine, and consider its place in “personalized medicine,” it is time to ask ourselves how we can aggregate this wealth of data into a single database for multiple users with different goals.

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“…Since the early discoveries of genes such as CFTR, DMD, FMR1, and PAH, there have been various efforts to create gene/diseasespecific mutation databases. These efforts started with locus-specific databases (LSDBs) (Fokkema et al 2005;Fokkema et al 2011;Pan et al 2011;Bean et al 2013;International Alport Mutation et al 2014;Lanthaler et al 2014) made by individual research groups for genes such as TP53 (Forbes et al 2011). In the last decade as sequencing costs dropped, new genes were rapidly discovered.…”

Section: Inherited Diseasesmentioning

confidence: 99%

Gene Variant Databases and Sharing: Creating a Global Genomic Variant Database for Personalized Medicine

Bean¹,

Hegde²

2016

Human Mutation

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Genotype-based databases for variants causing rare diseases

Cited by 11 publications

References 9 publications

Cholesterol-mediated Degradation of 7-Dehydrocholesterol Reductase Switches the Balance from Cholesterol to Vitamin D Synthesis

Cholesterol-mediated Degradation of 7-Dehydrocholesterol Reductase Switches the Balance from Cholesterol to Vitamin D Synthesis

Gene Variant Databases and Sharing: Creating a Global Genomic Variant Database for Personalized Medicine

Gene Variant Databases and Sharing: Creating a Global Genomic Variant Database for Personalized Medicine

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