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13

Genetic Modifiers That Affect Phenotypic Expression of Retinal Diseases

Malia M. Edwards, PhD, Dennis M. Maddox, PhD, Jungyeon Won, PhD, Jürgen K. Naggert, PhD, and Patsy M. Nishina, PhD

CONTENTS

INTRODUCTION

GENETIC MODIFIERS OF RETINAL DISEASES IN HUMANS

GENETIC MODIFIERS OF RETINAL DISEASES IN MICE AND OTHER MODEL

ORGANISMS

STRATEGIES AND EXAMPLES OF CLONING GENETIC MODIFIERS

SUMMARY AND PERSPECTIVES

REFERENCES

INTRODUCTION

Variability in onset, progression, severity, and phenotypic expression is commonly observed in many retinal diseases (Tables 1 and 2). Although interfamily variability may be caused by environmental or allelic differences, intrafamily variability, when a common mutation is segregating, may also be due to genetic modifiers (1–3). In contrast to independently acting alleles that may lead to an additive effect on disease severity or age of onset, genetic modifiers are defined as background genes that epistatically interact with a given disease genotype to affect phenotypic outcome. In general, allelic variability at modifier loci does not in itself produce a phenotype. A single gene or possibly a combination of genes in the same or parallel pathways as the mutant gene may act to create a final effect on the expression of the disease phenotype. These modifiers may enhance the effect of the mutation to cause a more severe mutant phenotype or an earlier onset, or conversely, delay or reduce the mutant phenotype even to the extent of completely restoring the wild-type (WT) condition.

Genetic modifiers have engendered excitement because the study and identification of these genes promise new insights into biological pathways that Mendelian disease genes act in and through which they cause pathologies (4,5). For example, knowing the molecular basis of a genetic modifier may help in better diagnosis and treatment of a

From: Ophthalmology Research: Retinal Degenerations: Biology, Diagnostics, and Therapeutics

Edited by: J. Tombran-Tink and C. J. Barnstable © Humana Press Inc., Totowa, NJ

237

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Table 1

Demonstrated or Probable Examples of Genetic Modification of Retinal Disease in Humans in which the Disease Haplotype or Genotype has been Established and Large Phenotypic Variability, Independent of Age, has been Observed

Primary

 

Phenotypic

Chromosomal location

 

mutation

Genotype

variability observed

or identity of modifier

References

 

 

 

 

 

Arrestin

1147delA

Oguchi’s Disease and ARRP: interfamilial

 

82

 

 

variability ranging from pigmentary retinal

 

 

 

 

degeneration in the midperipheral area with

 

 

 

 

or without macular involvement

 

 

Bestrophin

 

Vitelliform macular dystrophy 2 (VMD2):

 

83

 

 

phenotypes of 11 children from a homozygous

 

 

 

 

parent ranged from early onset cystoid macular

 

 

 

 

degeneration with accumulation of deeply and

 

 

 

 

irregularly pigmented yellow macular mass to

 

 

 

 

absence of clinical symptoms with pathological

 

 

 

 

EOG-values

 

 

Cadherin23

Arg1746Gln

USH1D: Severity and progression of RP is

 

84,85

 

 

highly variable

 

 

Clarin1

Asn48Lys

USH3A: Inter and intra-familial severity and

 

86

 

 

progression of RP noted

 

 

Elongation of very

5 bp deletion

Stargardt 3 (STGD3): phenotypes range from

Co-inheritance of a mutation

87,88

long chain fatty acids

 

Stargardt-like macular dystrophy to pattern

in (ABC4) increases disease

 

-like4 (ELOVL4)

 

dystrophy in related families

severity of STGD3

 

Fascin, sea urchin,

208delG

ADRP or ADMD

ATP-binding cassette

89

homology of, 2

 

 

 

 

(FSCN2)

 

 

 

 

Guanylate cyclase

Pro50Leu

Dominant cone (COD3) or cone-rod dystrophy:

 

90

activator 1A

 

minimal effects to macular function

 

 

(GUCA1A)

 

to cone-rod dystrophy observed in a family

 

 

Guanylate cyclase

Gly157Arg

Different forms or retinal diseases

 

91

activator 1LB

 

are observed, ADRP and ADMD

 

 

(GUCA1B)

 

 

 

 

239

Peripherin/RDS

Leu85Pro

Retinal disease: variability ranging from RP,

 

 

pattern dystrophy, fundus flavimculatus,

 

 

and macular degeneration

(PAP-1) protein

His137Leu

Retinitis pigmentosa 9 (RP9): in the original

target of Pim-1

 

large pedigree reported, phenotypes ranged

kinase

 

from minimally affected with no symptoms,

 

 

moderately affected with mild symptoms,

 

 

abnormal ERGs, and equal loss of rod and

 

 

cone function in affected areas of the retina;

 

 

and severely affected with extinguished ERGs

 

 

and barely detectable dark adapted static

 

 

threshold sensitivities

RP1

Arg677Ter

Retinitis Pigmentosa 1 (RP1): intra and interfamilial

 

 

variability in patients ranging from degeneration,

 

 

initially of rods, in the far peripheral inferior nasal

 

 

retina, to minimal or absence of disease

Retinoschisin

375-378delAGAT

X-linked retinoschisis: variability in disease

 

 

progression

Tissue inhibitor of

Ser181Cys

Sorsby fundus dystrophy (SFD): founder

metalloproteinase 3

 

effect in which families in British Isles, Canada,

(TIMP3)

 

United States, and South Africa with variation in

 

 

phenotype including white to yellow fundus spots

 

 

accompanying disciform macular degeneration,

 

 

absence of fundus spots, or yellow deposits

 

 

associated with atrophic macular degeneration

Diallelic inheritance observed

6,15–17

with rod outer segment membrane protein 1 (ROM1)

10,92

93

94

7–9,95

ARPP-autosomal recessive retinitis pigmentosa, EOG-electrooculography, USH-usher syndrome, ADMD-autosomal dominant mocular dystrophy.