Here are a few examples wherein rare, monogenic diseases can be caused by errors in any one of several different genes:
- Tuberous sclerosis is an inherited monogenic rare syndrome that produces multiple benign hamartomas, as well as certain types of cancers. The genetic basis of tuberous sclerosis involves bi-allelic inactivation of either of two unlinked genes that seem to have equivalent pathogenic roles. The genes are TSC1 (encoding hamartin) and TSC2 (encoding tuberin). In this disease, the hamartin and tuberin genes lock together in a protein complex. A defect in either gene disrupts the same pathway (1).
- Bardet-Biedl syndrome is characterized by rod-cone dystrophy, obesity, polydactyly, and a variety of organ abnormalities. The various forms of Bardet-Biedl syndrome are accounted for by mutations in one of at least 14 different genes. Although the underlying pathogenesis of Bardet-Biedl syndrome is yet to be clarified, there is evidence to suggest that each of the gene mutations known to cause Bardet-Biedl produce a defect in the basal body of ciliated cells (2). Such defects produce the pleiotropic phenotype that characterizes Bardet-Biedl syndrome.
- Li-Fraumeni syndrome is an inherited cancer syndrome characterized by an increased risk of developing such common cancers as breast cancer, lung cancer, colon cancer, pancreatic cancer, and prostate cancer. Various types of rare cancers associated with the Li-Fraumeni syndrome include soft tissue sarcomas, osteosarcomas, brain tumors, acute leukemias, adrenocortical carcinomas, Wilms tumor, and phyllodes tumor of breast. The observation that common cancers and rare cancers having a common underlying genetic cause would seem to indicate that a rare genetic cause of a common disease can sometimes occur within a gene that is known to cause a rare disease.
Li-Fraumeni syndrome was originally believed to be caused exclusively by mutations in the TP53 gene encoding protein p53. TP53 is an example of a tumor suppressor gene. The absence of a tumor suppressor reduces the cell's normal ability to suppress cellular events that increase the susceptibility of cells to cancer. In the case of the p53 gene, loss of activity reduces the ability of cells to undergo apoptosis, a process by which cells commit suicide following DNA damage. By continuing to survive and divide, damaged cells contribute to a subpopulation of cells at risk for progressing through the stages of carcinogenesis. As it turns out, mutations in genes other than TP53 can produce a syndrome similar to, if not indistinguishable from, Li-Fraumeni syndrome. In addition to TP53, the genes that produce forms of Li-Fraumeni syndrome include CHEK2 and BRCA1 (3). In all three cases, the resulting syndrome results in a very high risk for breast cancer (4). All three genes have similar functions: controlling whether cells live or die following DNA damage.
- Retinitis pigmentosa is a group of inherited conditions characterized by the progressive loss of photoreceptor cells in the retina. Rhodopsin consists of the protein moiety opsin and a reversibly covalently bound cofactor, retinal (5). More than 100 mutations in the rhodopsin gene account for about 25% of cases. About 150 mutations have been reported in the opsin gene. Other mutated genes causing variants of retinitis pigmenotosa involve pre-mRNA splicing factors, as well as post-translational errors in protein folding and other errors of chaperone proteins. Mutations in any one of more than 35 different genes can cause variant forms of retinitis pigmentosa. Retinitis pigmentosa is unusual for being a disease that can be inherited as an autosomal dominant, autosomal recessive, or X-linked disorder. Digenic and mitochondrial forms of retinitis pigmentosa have been described, and the disease can appear as a solitary disorder or as part of a multi-organ syndrome (e.g., NARP syndrome of neuropathy, ataxia, and retinitis pigmentosa caused by a mutation in the mitochondrial DNA gene MT-ATP6).
Why there are so many forms of retinitis, with such a large repertoire of disease-causing genes, is somewhat of a mystery. Most of the genes causing various forms of retinitis pigmentosa express constituents of specialized photoreceptors found exclusively in retinal photoreceptor cells (e.g., rhodopsin). Other genes that cause retinitis pigmentosa are active in many different cells (e.g., splicing factors). The outer segment of rod photoreceptors are continuously shed from the tips of cells and replaced by new segments. Rods are extraordinarily dependent on maintaining a high rate of self-renewal, and small deficiencies in cell synthesis may precipitate the loss of these cells (6), (7), (8).
- Epidermolysis bullosa is an inherited disease characterized by blistering of the skin and mucosal membranes (e.g., mouth). It is always caused by a defect causing the epidermis to be poorly anchored to the underlying dermis. Over 300 gene defects can result in epidermolysis bullosa. Depending on the variant form of the disease, any of several different genes may serve as the underlying cause (e.g., COL, PLEC, Desmoplakin genes). There is also an autoimmune form of epidermolysis bullosa acquisita, wherein antibodies target Type VII collagen, a component of the basement membrane glue that helps bind epidermis with dermis.
There are also instances in which a rare phenotypic condition occurs as a component of multiple syndromes, each caused by a different genetic mutation. For example, inherited hemophagocytic lymphohistocytosis is a component of Chediak-Higashi syndrome and of Griscelli syndrome. Hemophagocytosis is the pathological phagocytosis (i.e., engulfment) of red blood cells by macrophages. Acquired hemophagocytic lymphohistocytosis can occur in Letterer-Siwe disease (9). In all cases, the final pathogenetic steps of these phenotypically related diseases involves the hypersecretion of cytokines by lymphocytes and macrophages, precipitating a severe, and life-threatening, inflammatory response, that includes hemophagocytosis.
In instances where a combined gene deficiency is found, the root cause may be a microdeletion, that deletes multiple genes, at once. Alternately, a combined deficiency may be caused by a pleiotropic gene that controls the synthesis of several different proteins. In combined factor V and factor VIII clotting factor deficiency, a defect in either the LMAN1 OR MCFD2 genes results in deminished transport of factor V and factor VIII from the endoplasmic reticulum to the Golgi apparatus. Hence, the post-translational processing of both these factors is incomplete, and a combined deficiency results. The gene products of MCFD2 and LMAN1 form a cargo receptor complex that acts on a similar set of proteins. Hence, mutations in either gene can produce the same combined deficiency of factor V and factor VIII (10).
The number of rare genetic syndromes that can be caused by any one of several different genes is quite long. A few additional examples are listed here.
- Autosomal dominant cutis laxa can be caused by a mutation of the elastin gene or the fibulin-5 gene.
- Hypotrichosis simplex of the scalp can be caused by mutation in the CDSN gene or the KRT74 gene.
- Oguchi disease can be caused by a mutation oin the arrestin gene or the rhodopsin kinase gene.
- Autosomal dominant form of throbocytopenia can be caused by a mutation in the ANKRD26 gene, or the cytochrome c gene.
The diseases discussed in this section are examples of disease convergence, in which different underlying processes eventually converge to a common phenotype.
Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.
- Jules Berman (copyrighted material)
key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, disease complexity, common diseases, monogenic disease, disease genetics, jules j berman
 van Slegtenhorst M, Nellist M, Nagelkerken B, Cheadle J, Snell R, van den Ouweland A, et al. Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum Mol Genet 7:1053-1057, 1998.
 Ansley SJ, Badano JL, Blacque OE, Hill J, Hoskins BE, Leitch CC, et al. Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome. Nature 425:628-633, 2003.
 Silva AG, Ewald IP, Sapienza M, Pinheiro M, Peixoto A, de N brega AF, et al. Li-Fraumeni-like syndrome associated with a large BRCA1 intragenic deletion. BMC Cancer 12:237, 2012.
 Walsh T, Casadei S, Coats KH, Swisher E, Stray SM, Higgins J, et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA 295:1379-1388, 2006.
 Hubbard R, Wald G. The mechanism of rhodopsin synthesis. Proc Natl Acad Sci USA.37:69-79, 1951.
 Faustino NA, Cooper TA. Pre-mRNA splicing and human disease. Genes and Dev 17:419-437, 2003.
 Korenbrot JI, Fernald RD. Circadian rhythm and light regulate opsin mRNA in rod photoreceptors. Nature 337:454-457, 1989.
 Tanackovic G, Ransijn A, Thibault P, Abou Elela S, Klinck R, Berson EL, et al. PRPF mutations are associated with generalized defects in spliceosome formation and pre-mRNA splicing in patients with retinitis pigmentosa. Hum Mol Genet 20:2116-2130, 2011.
 Dufourcq-Lagelouse R, Pastural E, Barrat FJ, Feldmann J, Le Deist F, Fischer A, et al. Genetic basis of hemophagocytic lymphohistiocytosis syndrome (Review). Int J Mol Med 4:127-133, 1999.
 Zhang B, McGee B, Yamaoka JS, Guglielmone H, Downes KA, Minoldo S, et al. Combined deficiency of factor V and factor VIII is due to mutations in either LMAN1 or MCFD2. Blood 107:1903-1907, 2006.