This webpage was produced as an assignment for an undergraduate course at Davidson College.
In July, 2005 a mutation in the MFRP gene was linked to an inherited disorder that causes an exteme hyperopia, or farsightedness. Several medical news webs sites ran stories on the discovery and its implications. Here I look at the genetic disorder nanophthalmos, its correlation to MFRP, and the reporting done by two web publications.
Nanophthalmos (“Dwarf Eye”)
Nanophthalmos is a developmental disorder of the eye that impairs visual perception. Also known as “dwarf eye”, it causes extreme farsightedness, or hyperopia, in affected individuals. Studies have traced the loss of vision acuity to a reduced distance between the cornea and retina (Sundin et al., 2005). Outside of the decreased axial length and some secondary complications, nanophthalmic eyes appear relatively normal. The condition’s relationship with general losses of visual perception remains unclear (Sundin et al, 2005).
The disorder’s genetics roots have been understood for thirty years (Medindia.com). Both dominant and recessive inheritance patterns have been observed in families carrying the nanophthalmos mutation. Previous research performed with the dominant version of nanophthalmos traced the associated gene to the NNO1 locus. The specific gene, however, remains unknown (Sundin et al., 2005).
Proceedings of the National Academy of Sciences of the United States of America
A recent article published in PNAS by Sundin et al. describes a link between MFRP and an autosomal recessive form of nanophthalmos. Through the study of the gene’s inheritance in an Amish-Mennonite family, Sundin et al. links a recessive form of the disease to the MFRP gene located at 11q23.3.
The abstract of the PNAS article opens with four sentences describing the phenotype associated with nanophthalmos. Since the paper deals with a mutation, the observed phenotype becomes extremely important for interpretation and application of the information. The authors emphasize that the nanophthalmic phenotype appears mostly limited to a particular aspect of eye-development.
The authors constantly relate their discovery to other areas of research. For example, the first sentence of the introduction describes the development of the eye to “the general problem of how organs regulate their size” (Sundin et al., 2005). They are relating the specific issue of eye development with the broader context of how organ systems develop with correct proportions. This reminder shows that the results have relevance beyond the study of an obscure eye-disorder. The authors also run through the current understanding of ocular development and past obstacles encountered in its study.
Both dominant and recessive inheritance patterns have been observed in families that carry the disorder. The dominantly inherited form has been mapped to the NNO1 locus, which spans 27 Mb on chromosome 11 (Orthman et al., 1998). The region contains a candidate gene, VMD2, that functions in macular dystrophy (Sundin et al., 2005).
The final paragraph of the introduction describes the history of genetic research conducted on nanophthalmos. VMD2, a macular dystrophy gene, was discovered as a candidate gene for the dominant form of nanophthalmos in 2004 (Sundin et al., 2005). The authors make a clear distinction between the recessive version of nanophthalmos and those that display dominant or semi-dominant inheritance patterns. The background information gives additional context to view the discovery and emphasizes that MFRP is not the only cause of the disorder.
In their study, Sundin et al. tested an Amish-Mennonite family that exhibited an autosomal recessive inheritance pattern of nanophthalmos. The team used several techniques to study the phenotypes of both healthy and afflicted members. Unaffected family members showed normal phenotypes, suggesting that the inherited form of the disease is purely recessive (Sundin et al., 2004). The team genotyped 16 members from the family using short tandem repeat markers. Logarithm of odds scores showed a strong linkage to a single region on chromosome 11, which led researchers to the MRFP gene. Affected individuals in the family were homozygous for a frameshift insertion in exon 10 of the MRFP gene with the exception of one uncle, who was heterozygous but still developed nanophthalmos.
Analysis of 26 other nanophthalmos families found 2 additional families that carried mutations at the MFRP gene. The recessive nature of the mutations hold in both additional families. MFRP is expressed at high levels in the eye and low levels in the brain. Although the nanophthalmos phenotype suggests a cause associated with connective tissue, MFRP functions in the retinal pigment epithelium. Sundin et al. speculate on the possible function of the MFRP gene. Finally, the research team suggests that the lone heterozygote to exhibit nanophthalmos may possibly carry a second, less-severe mutation.
Figure 1: A possible three-demensional structure of the MFRP protein. Although it represents a novel protein, Sundin et al. speculate it might function as a receptor for Wnt molecules, which are involved in cell-signaling pathways (2005). Image courtesy of UCSF Mod Base.
VMD2 mutation causes dominant nanophthalmos
As mentioned in the PNAS article, VMD2 is a candidate gene for the dominantly inherited type of nanophthalmos. Yardley et al. found that mutations in VMD2 caused a type of nanophthalmos associated with the developmental disorder vitreoretinochoroidopathy (ADVIRC) in five separate families (2004). Like MFRP, the VMD2 gene is highly expressed in the retinal pigment epithelium (Noriko et al., 2005). The VMD2 gene is not limited to eye development, as the VMD2 protein appears to function in ion exchange across the membranes of airway epithelial cells (Duta et al., 2004).
Outside of the specifics of its cellular function, the VMD2 gene gives two major implications to further study of eye development and ocular disorders. First, the VMD2 gene’s function in multiple biological systems shows that eye development shares genes with other processes in the body. Thus, the research into eye development and associated disorders will draw heavily from other areas of research conducted on other systems throughout the body. Also, VMD2 shows that common cases of nearsightedness or farsightedness will not likely be traced to a single gene but rather to a collection of genetic factors.
The Mediandia.net report of the Sundin et al. study uses a questionable title: “Genetic Cause for Farsightedness Discovered.” The phrase overstates the study’s findings, since MFRP mutation is believed responsible for a only one type of hyperopia. Also, the first paragraph describes the research findings as the “gene expression responsible for extreme farsightedness in people.” Again, the article uses generalized terminology, perhaps to make the research’s findings seem more groundbreaking.
Although the article thoroughly describes the physiology associated with nanophthalmos, it omits much research and current genetic knowledge about the disorder. The article refers to MFRP mutations as “the gene expression” responsible for nanophthalmos, omitting mention of the VMD2 gene. In effect, the article suggests that a single genetic disorder results from a single mutated gene. Since nanophthalmos represents a complex disorder with multiple known genetic causes, the oversight hurts the scientific relevance of the find.
The article devotes a fair amount of text to the history of the John Hopkins study. The description gives the discovery historical context. Also, the final paragraph describes hopes for the future applications of the discovery. The article gives a solid historical context, even if a scientific context is lacking.
Healthday.com – “News for Healthier Living”
As its slogan suggests, Healthday.com relates medical news and information to the public without assuming any background in science. Health Day covered the MFRP find in an article entitled “Genetic Cause for Eye Disorder Uncovered”. The article’s main focus is the potential medical applications of the discovery. For example, the writer quotes Dr. Sundin, who expresses his hope that the discovery will aid in understanding the root causes of “nearsightedness and farsightedness.”
Unfortunately, the article does a poor job of relating both current scientific understanding and the process through which nanophthalmos was discovered. A single mention of the Amish-Mennonite family tree is the only reference to scientific methodology in the entire article. Also, VMD2 and other research conducted on nanophthalmos get no attention in the article.
The article contains several inaccuracies, including the statement that the MFRP gene is “located beneath the retina” (Thompson). In reality, the tissue beneath the retina is affected by the gene's activity. Also, like Medindia.com, the article reports MFRP to be the genetic cause for nanophthalmos. Sundin et al. were only able to identify mutations on the MFRP gene in a small subset of the families that carried the disorder. Nanophthalmos, as a disorder, results from mutations to at least two genes and possibly more.
One gene, one article
In reporting their discovery, Sundin et al. thoroughly relate the connection between MFRP and nanophthalmos to other areas of research. Giving scientific findings their proper context should be the goal of any paper (Kua et al., 2001). Both popular press articles that report on the discovery, however, omit peripheral scientific discoveries, including the knowledge that multiple genes function in nanophthalmos.
Although press articles have different aims than primary scientific literature, omission of related discoveries is doubly damaging when reporting genetics research. Gene interactions complicate the popularized notion that single genes correspond to particular traits. In the case of nanophthalmos, mutations in two genes are known to cause the developmental disorder.
The current one-gene, one-article paradigm does not give MFRP its proper context. The web publications and print news sources should aim to translate scientific findings into language that the public can understand (Kua 2001). The current practice of reporting genes independently, however, does not reflect reality. Unless the popular press begins to give genetic discoveries broader context, they will be unable to provide accurate scientific information to the public.
Duta, V., A.J. Szkotzk, D. Nahirney, and M. Duszyk. “The role of bestrophin in airway epithelial ion transport.” FEBS Letters 577: 551-554.
26 Aug. 2005. "Genetic Cause for Farsightedness Discovered". Medindia.com. <www.medindia.net/news/view_news_main.asp?x=4709>. 1 Sep. 2005.
Kua, E., M. Reder, and M.J. Grossel. “Science in the news: a study of reporting genomics.” Public Understanding of Science 13: 309-322.
Esumi N., Y. Oshima, Y. Li, P.A. Campochiaro, and D.J. Zack. “Analysis of the VMD2 promoter and implication of E-box binding factors in its regulation.” Journal of Biological Chemistry 279: 19064-73.
Pieper U., N. Eswar, H. Bradberg, M.S. Madhusudhan, F. Davis, A.C. Stuart, N. Mirkovic, M.A. Marti-Renom, A. Fiser, B. Webb, D. Greenblatt, C. Huang, T. Ferrin, A. Sall. "MODBASE, a database of anonnoed comparative protein structure models, and associated resources." Nucleic Acids Research 32: D217-D222.
Sundin, O.H., G.S. Leppert, E.D. Silva, J. Yang, S. Dharmaraj, I.H. Maumenee, L.C. Santos, C.F. Parsa, E.I. Traboulsi, K.W. Broman, C. DiBernardo, J.S. Sunness, J. Toy and E.M. Weinberg. "Extreme hyperopia is the result of null mutations in MFRP, which encodes a Frizzled-related protein ". PNAS102: 9553-58.
Thompson, D. 26 Aug. 2005. "Genetic Cause for Eye Disorder Uncovered". HealthDay.com. <http://www.healthday.com/view.cfm?id=527624>. 1 Sep. 2005.
Yardley J., B.P. Leroy, N. Hart-Holden, B.A. Lafaut, B. Loeys, L.M. Messiaen, R. Perveen, M.A. Reddy, S.S. Bhattacharya, E. Traboulsi, et al. “Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC)”. Investigative Ophthalmology and Visual Science 45: 3683-9.
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