Current Norrie Disease Research (From Norrie disease to Norrinopathies.)
Presentation Transcript
1. Wolfgang Berger 1st International Norrie Disease Conference Boston (MA), August 14
and 15, 2009
2. History and genetics of ND
a. first described in 1927 (Gordon Norrie)
b. comprehensive description by Mette Warburg in 1966
c. absence of male to male transmission
d. women are not affected (exceptions exist)
e. affected males are related through their mothers
f. X-linked reccessive mode of inheritance
g. 1985: linkage to DXS7
i. deletions of DXS7 and MAOA and/or MAOB
h. 1992: positional cloning of the NDP gene
3. NDP mutations and clinical outcome
a. mutations in the NDP gene can lead to:
i. classic ND (Berger et al., Hum Mol Genet, 1992; Meindl, Berger et al.,
Nat Genet, 1992)
ii. exudative vitreoretinopathy (EVR) (Chen et al., Nat Genet, 1993)
iii. retinopathy of prematurity (ROP) (Shastry et al., Arch Ophthalmol, 1997)
iv. Coats disease (Black et al., Hum Mol Genet, 1999)
4. Mutations in Exudative vitreoretinopathy (EVR)
a. prevalence: rare
i. incomplete blood vessel development (avascular
ii. periphery), -> hypoxia and neovascularization
iii. retinal folding and detachment, hemorrhages
iv. autosomal dominant, recessive and X-linked recessive
v. inheritance
b. Currently 3 Genes Known
i. NDP: Norrie disease pseudoglioma(Chen et al., Nat Genet, 1993)
ii. FZD4: Frizzled 4 (Robitaille et al., Nat. Genet., 2002)
iii. LRP5: low density lipoprotein receptor-related protein 5(Jiao et al., Am J
Hum Genet, 2004)
5. Retinopathy of prematurity (ROP)
a. normally, maturation of the retina proceeds in-utero and mature infants have a
fully vascularized retina
b. preterm infants frequently show incomplete vascularization of the retina (birth
weight < 1500 grams, gestational age < 32 weeks)
c. growth of abnormal new vessels that may regress, but frequently progress
d. retinal detachment and exudates
e. different stages (I-V, mild -> severe)
f. oxygen exposure is not the main risk factor for development of this disease
6. Overlapping symptoms of mutations in NDP, FZD4 and LRP5
7. Generation of a mouse model for ND
8. Blood vessel development in Ndph knockout mice
9. Abnormal vascular development in the retina
10. Lack of deep vessels in Ndph ko mice
11. Abnormal vascular development in the retina
12. Delayed and reduced outgrowth of the superficial vessels network
13. Delayed regression of hyaloid vessels
14. Summary
a. delayed development of the superficial retinal
b. blood vessels, lack of capillaries
c. lack of the deep and intermediate capillary networks
d. defect in angiogenic sprouting
e. delayed regression of the hyaloid vasculature