Developmental basis of nanophthalmos: MFRP Is required for both prenatal ocular growth and postnatal emmetropization.
BACKGROUND
Nanophthalmos is a genetic disorder characterized by very small, hyperopic eyes that are without gross structural defects. Recessive nanophthalmos is caused by severe mutations in the MFRP gene, which encodes a Frizzled-related transmembrane protein that is selectively expressed in the retinal pigment epithelium (RPE) and ciliary body.


RESULTS
For two MFRP -/- adults, we have obtained records of refraction that begin in early childhood. At the age of 6 months, one patient's eyes already had a refractive error of +12.25 D, and over the next 20 years this slowly increased to +17.50 D. Adults homozygous for null mutations in MFRP have eyes with axial lengths shorter than those of normal newborns. Furthermore, the unusually high curvature of their corneas is consistent with eyes that had been smaller than normal during late fetal development. MFRP protein was first detected at 14 weeks of gestation, when it was restricted to the posterior pole RPE. By 20 weeks gestation, MFRP expression had spread laterally, and was found throughout the RPE. MFRP protein was detected in both posterior and lateral RPE of the adult eye.


CONCLUSIONS
Embryonic function of the MFRP gene appears necessary for the eye to reach its full size at birth. Its onset of expression in the RPE during mid-gestation suggests that MFRP does not participate in early formation of the optic cup, and is consistent with a role in later growth and development of the eye. Patients without MFRP gene function exhibit no correction of refractive error during childhood, which suggests that this gene is essential for emmetropization, a complex process by which vision regulates axial growth of the eye.
Sundin
Olof H
OH
Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-92889, USA. osundin@jhmi.edu
Dharmaraj
Sharola
S
Bhutto
Imran A
IA
Hasegawa
Takuya
T
McLeod
D Scott
DS
Merges
Carol A
CA
Silval
Eduardo D
ED
Maumenee
Irene H
IH
Lutty
Gerard A
GA
D000328:Adult; D000375:Aging / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism; D047108:Embryonic Development; D005123:Eye / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D016368:Frameshift Mutation; D017353:Gene Deletion; D005808:Genes, Recessive; D005865:Gestational Age; D006720:Homozygote; D006801:Humans; D006956:Hyperopia / Q000196:embryology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D007223:Infant; D007231:Infant, Newborn; D007908:Lens, Crystalline / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008850:Microphthalmos / Q000196:embryology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D009799:Ocular Physiological Phenomena; D010857:Pigment Epithelium of Eye / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D012029:Refraction, Ocular; D014785:Vision, Ocular / Q000502:physiology; D000099274:Frizzled-Related Proteins
D008565:Membrane Proteins; C490110:MFRP protein, human; D000099274:Frizzled-Related Proteins