Retinitis pigmentosa - 50,000-100,000 Americans
Night blindness, loss of midperipheral vision (where rods are in high concentration)
autosomal and x-linked, dominant and recessive
there is a staggering list Table (Bird)
Candidate gene analyses, SSCP = single stranded conformational polymorphism,
rely on screening many unrelated people
Figure from Huang et al.
Some genes which are obvious candidates are in the phototransduction cascade
Figure from Farber
"Membrane" proteins usually inferred from Kyte-Doolittle hydrophobicity plots
rhodopsin missense mutations cause 20-20% of ADRP
there is a rhodopsin null mutation which causes ARRP
Figure from Bird covers the vast number of opsin mutants found, many studies

M. E. McLaughlin et al., Recessive mutations in the gene encoding the beta-subunit of rod phosphodiesterase in patients with retinitis pigmentosa. Nature Genetics 4, 130-134, 1993
gene has 22 exons
Figure from Farber - note that it is really odd that there are 2 defects in rd mice
screen 7 exons so far in 99 patients
Gln298X nonsense, Arg531X (nonsense), Pro496(1-pb del), His557Tyr

S. H. Huang et al., Autosomal recessive retinitis pigmentosa caused by mutations in the alpha subunit of rod cGMP phosphodiesterase. Nature Genetics 11, 468-471, 1995
22 exons on human chromosome 5q31.2-34
ARRP Tyr583Ter nonsense,Ser344Arg nonsense, Trp561Ter nonsense

T. P. Dryja et al., Mutations in the gene encoding the a subunit of the rod cGMP-gated channel in autosomal recessive retinitis pigmentosa. Proc. Natl. Acad. Sci. USA 92, 10177-10181, 1995
10 exons - SSCP
find nonpathological changes - 3 silent, 2 missense, 2 1-base intron changes
and one variation in length of a poly-A repeat in an intron
5 pathological changes - 3 nulls and 2 missense

also there are other animal models which suggest candidate genes like the rds mouse
Figures from Molday
R. S. Molday, Peripherin/rds and rom-1: Molecular properties and role in photoreceptor cell degeneration. Chapter 11 in Progress in Retinal and Eye Research 13, 271-299, 1994
rds on short arm of human chromosome #6, has 2 introns
346 a.a. polypeptide with 4 membrane spans
rom-1 on human chromosome 11q13
351 a.a.
Kajiwara et al., Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROM1 loci. Science 264, 1604-1608, 1994.
Peripherin: Pro219del, Pro216Leu and Ser212Gly -> ADRP
Leu185Pro in peripherin like autosomal dominant but transmit only 1/4 of offspring
Peripherin on human chromosome 6p
ROM1 on human chromosome 11q find Gly80(1-bp ins) and Leu114(1-bp ins)
cause premature stop at 131 - early - probably null
If both genes mutant heterozygous, patient has RP
if only one, people are asymptomatic, do not know about homozygous for either

Age related macular degeneration (ARMD)

R. Allikmets et al., Mutation of the Stargardt's disease gene (ABCR) in age-related macular degeneration. Science 277, 1805-1807, 1997
also
E. Pennisi, Gene found for the fading eyesight of old age (Research news, Human genetics) Science 277, 1765-1766, 1997
"Macula" is a term for the central part of the retina, like fovea
Macular degeneration (11 million Americans) comes in 2 types:
(1) wet (20%) (exudative) can be an emergency treatable with laser
one model, Sorsby's fundus dystropht - TIMP3 - tissue inhibitor of metalloproteinase-3
(2) dry (80%) with drusen of debris under retina
a gene on 1p21 with 51 exons codes STDG1 also ABCR
=ATP-binding casette transporter-retina
TRANSPARENCY Fig 1 from paper -different mutations for Stargardt's vs AMD
looks like CFTR
it is also the protein called "rim protein" RmP (in rods)
There is a lot of controversy over this point, and critics claim that in such a large gene, there can be neutral mutations, so it is necessary to show that the genetic alteration cosegregates with the disorder.
But the work goes on (Shroyer et al., 2002). This is a huge gene (50 exons). There is a missense mutation V767D in an individual who also has W1408R and R1640W, and this appears to be null and causes RP.
This protein is of likely importance as a transporter of retinal based on the fact that retinal stimulates ATP hydrolysis (Sun et al., 1999)

References

R. Allikmets et al., Mutation of the Stargardt's disease gene (ABCR) in age-related macular degeneration. Science 277, 1805-1807, 1997

A. C. Bird, Retinal photoreceptor dystrophies LI Edward Jackson Memorial Lecture. Am. J. Ophthalmology 119, 543-562, 1995

T. P. Dryja et al., Mutations in the gene encoding the a subunit of the rod cGMP-gated channel in autosomal recessive retinitis pigmentosa. Proc. Natl. Acad. Sci. USA 92, 10177-10181, 1995

D. B. Farber, From mice to men: The cGMP phosphodiesterase gene in vision and disease (The Proctor Lecture). Investigative Ophthalmology and Visual Science 36, 263-275, 1995

S. H. Huang et al., Autosomal recessive retinitis pigmentosa caused by mutations in the alpha subunit of rod cGMP phosphodiesterase. Nature Genetics 11, 468-471, 1995

Kajiwara et al., Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROM1 loci. Science 264, 1604-1608, 1994.

M. E. McLaughlin et al., Recessive mutations in the gene encoding the beta-subunit of rod phosphodiesterase in patients with retinitis pigmentosa. Nature Genetics 4, 130-134, 1993

R. S. Molday, Peripherin/rds and rom-1: Molecular properties and role in photoreceptor cell degeneration. Chapter 11 in Progress in Retinal and Eye Research 13, 271-299, 1994

E. Pennisi, Gene found for the fading euesight of old age (Research news, Human genetics) Science 277, 1765-1766, 1997

N. F. Shroyer et al., Null misense ABCR (ABCA4) mutations in a family with Stargardt disease and retinitis pigmentosa, Invest. Ophthalmol. Vis. Sci., 42, 2757-2761

Sun, H., RS Molday and J. Nathans, Retinal stimulates ATP hydrolysis by purified and reconstructed ABCR, the photoreceptor-specific ATP-binding cassette transporter responsible for Stargardt disease. J. Biol. Chem., 274, 8269-8281, 1999

This page was last updated on January 8, 2002

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