Wagner syndrome is a dominant autosomal disease. That means that 50% of the offspring is affected, boy or girl.
The gene responsible for Wagner syndrome is the mutated Versican gene on the long arm (q) of the 5th chromosome 5q14.3. To be precise: from base pair 82.767.529 to 82.877.799
genetics
glossary
(ncbi-gene reviews)
isoforms
The protein products of different versions of messenger RNA created from the same gene by employing different promoters, which causes transcription to skip certain exons. Since the promoters are tissue-specific, different tissues express different protein products of the same gene.
RNA
synonym:
ribonucleic acid
The molecule synthesised from the DNA template; contains the sugar ribose instead of deoxyribose, which is present in DNA; three types of RNA exist, messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA)
DNA
synonym: deoxyribonucleic acid
The molecule which encodes the genes responsible for the structure and function of an organism and allows for transmission of genetic information from one generation to the next
gene
The basic unit of heredity, consisting of a segment of DNA arranged in a linear manner along a chromosome. A gene codes for a specific protein or segment of protein leading to a particular characteristic or function.
transcription
he process of synthesising messenger RNA (mRNA) from DNA
splicing
synonym:
splicing mutation
The process by which introns, non-coding regions, are excised out of the primary messenger RNA transcript and exons (i.e. coding regions) are joined together to generate mature messenger RNA
exon
Coding sequence of DNA present in mature messenger RNA
nucleotide
A molecule consisting of a nitrogenous base (adenine, guanine, thymine, or cytosine in DNA; adenine, guanine, uracil, or cytosine in RNA), a phosphate group, and a sugar (deoxyribose in DNA; ribose in RNA). DNA and RNA are polymers of many nucleotides.
Wagner & Stickler, confusion ended
Before the gene was found, there has been considerable confusion between Wagner en Stickler.
Researchers assumed that Wagner and Stickler were having a common cause. Sometimes Wagner syndrome was named as ocular-only Stickler.
Irene Maumenee (University of Illinois, Chicago, USA) had a different approach. She thought that there must be two different kind of disorders: ocular only and disorders with also facial-skeletal and other abnormalities.
These days four Stickler genes are identified. The main one causing 75% of the Stickler cases, COL2A1, was first mentioned by Clair Francomano (Baltimore, USA) in 1987. COL11A2, was found as the cause of non-ocular Stickler by Han Brunner (Nijmegen, the Netherlands) in 1994. COL11A1 was found by Susanna Annunen (Oulu, Finland) in 1999. And finally Guy Van Camp (Antwerp, Belgium) described in 2006 the COL9A1 gene as the cause of the recessive Stickler variant.
It was clear that the Dutch and Japanese Wagners had something different. It took till 2005 to find the cause of Wagner in the Versican gene.
Erosive vitreoretinopathie
As you can see erosive vitreoretinopathy is caused by the same gene as Wagner. It is considered an allelic disorder: a different mutation of the same gene.
ERVR was first described in 1994 by Brown at al (Department of Ophthalmology, University of Iowa, College of Medicine, Iowa City, USA). He believed it to be a new clinical entity.
The Dutch group headed by Frans Cremers found that the
c.4004-5T>C variant is present in 4 large Wagner disease families and in the Dutch ERVR family. Genetic analysis showed that all these families share the same ancestor with this CSPG2/Versican variant (Mukhopadyay et al. 2006). This means that ERVR is in fact NOT a distinct clinical entity It is not understood why the same genetic variant gives rise to differences in severity.
On the page ‘symptoms’ we will explain the at first sight obvious ocular differences between Wagner and ERVR, as mentioned in publications.
Wagner syndrome
page last modified Auh 6th 2014
It causes a different kind of splicing. Wagner syndrome is the only known disorder caused by a mutation of the Versican gene. It is estimated that this mutation is perhaps not older than 1000 years.
image nlm-nih / usa (modified)
genetic testing
Can be done in Zürich, Switzerland and in Nijmegen, the Netherlands. See developments
fig. Vitreoretinopathy-associated mutations in VCAN and their effects on splice variants and protein isoforms.
Under normal conditions, differential splicing leads to four transcript variants and protein isoforms V0, V1, V2, or V3, depending on the presence of exon 7 (red) and/or exon 8 (green). Attachment of glycosaminoglycan residues (GAGs; black vertical lines) modifies the protein to function in water inclusion. Mutations (black single-line vertical arrows pointing downward) lead to skipping of exon 8 and yielding increased amounts of variants V2 and V3. The effects of the mutations on isoform expression (decrease or increase) are displayed by wide vertical turquoise-filled arrows (right). An imbalanced quantitative ratio of these variants is a result of the mutations. Schematic lines are not drawn to scale.
Exon sizes are given in nucleotides (nt). Protein isoform length is given by number of amino acid (aa) residues beneath each isoform. c.4004 and c.9265 are the first and last nucleotides of exon 8.
The mutation in the Dutch Wagners is in intron 7 (c.4004-5T>C) as is the mutation in the Japanese Wagners (c.4004-2G>A). So it is the 5th (Dutch) or 2nd (Japanese) nts before exon 8 starts. In the Swiss Wagners and in the family from Cambridge, UK the mutation is in intron 8 (c.9265+1G>A). So with them it is the first nucleotide after exon 8 ended. The new family from North Caroline (US) also has a mutation in this ‘Hot-Spot’, only with them the G is replaced with a T:
c.9265+1G>T.
(with courtesy Barbara Kloeckener-Gruissem et al in gene reviews)
heredity
mutations
Untill now 11 different mutations have been found in 14 different families. In 2013 two new French families were identified, one of them with a de novo mutation (a person whose parents were not affected). In China one family with three affected family members was found in a nationwide (!) research. That seems to underline the rarity of Wagner syndrome.
The most frequent mutation, that in the Neteherlands, is in intron 7
(c.4004-5T>C) just as the mutation in the Japanese Wagners
(c.4004-2G>A). This mutations concern 5 (NL) or 2 (JP) nucleotides before the beginning of exon 8. With the Suisse Wagners and the Brittish family from Cambridge the mutation is in intron 8
(c.9265+1G>A). So the first nucleotide after exon 8. The new family from Noord-Caroline (USA) also has a mutation on this ‘Hot-Spot’, but with them the first G turned into a T: c.9265.+1G>T.
