Molecular Genetics of the Hereditary Vitreoretinopathies

The classification in Table 1 Correlates with genotype. Table 3 Lists the causative genes that have been identified to date in the hereditary vitreoretinopathies with the protein affected (Table 3).

Mutations in genes coding for the structural components of vitreous result in a hereditary vitreoretinopathy. In common with connective tissues in other parts of the body, vitreous is composed of an extracellular matrix with relatively few cells and the arrangement of the collagenous proteins, along with the high water content, maintains transparency. Vitreous collagen fibrils are heterotypic and have a core of type II and V/XI collagen, with type IX collagen on the surface. Mutations in genes coding for chains which comprise these three types of collagen result in the most common hereditary vitreoretinopathy, Stickler syndrome.

The majority of patients with Stickler syndrome have type 1 Stickler syndrome which is part of the spectrum of type II collagen disorders along with Kniest dysplasia and SEDC. Most have premature termination mutations of the COL2A1 gene and are characterized by a membranous vitreous appearance on biomicroscopy. Other pedigrees exhibit a different beaded vitreous phenotype and are associated with mutations in one of the genes coding for type V/XI collagen (COL11A1). Type 1 Stickler syndrome, in the majority of cases, results from hap-loinsufficiency from nonsense-mediated decay through point mutations or frameshifts, whereas type 2 Stickler syndrome results from dominant negative mutations.

Collagen types II and IX are expressed in both vitreous and cartilage, so Stickler syndrome is characterized by an

Figure 13 Pseudoexotropia in Wagner syndrome.

Figure 14 Retinal folds seen in familial exudative vitreoretinopathy.

Ocular and skeletal phenotype. Cartilage also contains type XI collagen, which is similar to the type V/XI collagen of vitreous and they share the a1(XI) chain that is encoded by COL11A1; so mutations in this gene have an ocular and skeletal phenotype. A subgroup of Stickler syndrome, designated predominantly ocular, or ocular-only, has been shown to result from mutations of COL2A1 which are preferentially expressed in ocular tissues. Exon 2 of COL2A1 is spliced out of cartilage type II collagen and therefore mutations in exon 2 have a normal skeletal phenotype while displaying the characteristic ocular features of Stickler syndrome. Prior to detailed understanding of the molecular genetics of Stickler syndrome, the existence of patients demonstrating Ocular features without systemic findings was a source of confusion between Stickler syndrome and other vitreoret-inal degenerative conditions without systemic involvement.

Fibrillins are one of the main constituents of extracellular microfibrils and these provide structural support in many tissues. Mutations in FBN1, encoding for fibrillin 1, are the major cause of Marfan syndrome. Mutations in a second gene, transforming growth factor beta receptor II (TGFBR2), have been found in patients fulfilling the clinical criteria for Marfan syndrome, but the mechanism for this remains to be clarified.

Wagner syndrome is a further example of a hereditary vitreoretinopathy which results from a mutation in a gene coding for a structural protein in the vitreous. CSPG2 encodes the core protein of a chondroitin sulfate proteoglycan called versican. Versican binds hyaluronan and therefore may contribute to the structure of the vitreous. Versican undergoes alternative splicing and several splice variants have been identified in the eye. All causative mutations to date affect the splicing of exon 7 of the CSPG2 gene which represents one of two glycosamino-glycan attachment sites. In Wagner syndrome there is an Altered appearance to the vitreous, and progressive retinal dysfunction and hemeralopia even in the absence of retinal detachment, suggesting that versican has additional roles to being a structural component of the vitreous.

FEVR is also genetically heterogenous. All the causative genes to date in FEVR code for proteins involved in the Wnt signaling pathway. Frizzled homolog 4 (Drosophila) (FZD4) is a presumptive Wnt receptor, lipoprotein-receptor-related protein 5 (LRP5) can transduce Wnt signaling in vitro, and Norrie disease (Pseudoglioma) (NDP) encodes for norrin. Norrin is present in extracellular matrices and is thought to act as a ligand-receptor pair with FZD4. Although unrelated to Wnts, norrin may act on the Wnt signaling pathway through the frizzled receptor. Wnt receptors are implicated in retinal neovascularization. NDP mutations can also cause Norrie disease (characterized by incomplete retinal vascularization along with more extensive retinal degenerative changes, microphthalmia, and progressive mental disorder).

In general, the molecular genetics of the hereditary vitreoretinopathies demonstrate how mutations of key genes involved in ocular development and structure can result in different phenotypes. Goldmann-Favre syndrome is allelic with enhanced S-cone dystrophy (ESCD). The responsible gene encodes a retinal nuclear receptor involved in signaling pathways. ADVIRC is allelic with Best’s macular dystrophy and results from mutations in the VMD2 gene encoding a transmembrane chloride channel. Snowflake vitreoretinal dystrophy is caused by a mutation in a gene encoding a different transmembrane channel.

Of the hereditary vitreoretinopathies associated with skeletal abnormalities, the majority are inherited as an autosomal dominant trait. The exceptions are Stickler

Table 3 Causative genes identified to date and the protein affected in the hereditary vitreoretinopathies


OMIM number

Causative gene

Affected protein

First reference

Stickler syndrome



Type II collagen

Ahmad et al. (1991)



Type XI collagen

Richards et al. (1996)



Type IX collagen

Van Camp et al. (2006)

Kniest dysplasia



Type II collagen

Winterpacht et al. (1993)




Type II collagen

Tiller etal. (1995)

Knobloch syndrome



Type XVIII collagen

Sertie et al. (2000)

Marfan syndrome




Dietz et al. (1991)


Transmembrane receptor

Boileau et al. (1993)

Wagner syndrome



Chondroitin sulfate proteoglycan

Miyamoto et al. (2005)

Goldmann-Favre syndrome



Retinal nuclear receptor

Sharon et al. (2003)




Wnt receptor

Robitaille et al. (2002)



Wnt receptor

Toomes et al. (2004)



Wnt receptor ligand

Fullwood et al. (1993)





Yardley et al. (2004)

Snowflake vitreoretinopathy



K+ transporter

Hejtmancik et al. (2008)

Syndrome specifically associated with COL9A1 mutations, and Knobloch syndrome, both of which have an autosomal recessive pattern of inheritance. Wagner syn-drome/erosive vitreoretinopathy is inherited in an autosomal dominant pattern. Favre-Goldmann syndrome/ ESCD is autosomal recessive. Vitreoretinopathies associated with abnormal retinal vascularization are aGain inherited as autosomal dominant traits for the majority with the one exception being an X-linked form of FEVR. Snowflake vitreoretinal dystrophy is autosomal dominant.

See also: Molecular Composition of the Vitreous and Aging Changes; Rhegmatogenous Retinal Detachment; Secondary Photoreceptor Degenerations; Vitreous Anatomy, Aging, and Anomalous Posterior Vitreous Detachment.

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