What’s in a name? (original) (raw)
While DBA is phenotypically and genetically heterogeneous, a pathogenic mutation in an RP subunit gene usually consolidates the clinical diagnosis. In individuals without RP gene mutations, the diagnosis is based purely on clinical findings after a variety of other conditions that cause erythroid hypoplasia are excluded (14). The patients described by Sankaran et al. received their clinical diagnosis from DBA experts according to current consensus guidelines. Moreover, mutations in GATA1 and RP genes clearly produce overlapping phenotypes (Figure 3). These findings raise the question of whether GATA1 should be included as a new “DBA gene.” Alternatively, should GATA1 gene mutations be excluded before a clinical diagnosis of DBA is made? Both views have their justifications, shortcomings, and precedence in the nomenclature of human disease. Suddenly becoming “not DBA” or a “different type of DBA” through new genetic testing can unsettle patients and physicians when a diagnosis that they have come to accept potentially unravels.
Shared and distinct phenotypes in congenital red cell aplasia caused by mutations in RP genes and in GATA1. eADA, erythrocyte adenosine deaminase activity, MCV, mean corpuscular volume; Hb, hemoglobin; TMD, transient myeloproliferative disorder.
Medical syndromes are typically defined by signature constellations of physical and laboratory findings. Most were named years ago according to clinical features (e.g., dyskeratosis congenita) or after physicians who first described them (e.g., DBA or Fanconi anemia [FA]). More recently, molecular studies have revealed that many of these syndromes are genetically heterogeneous, with causative mutations occurring in one of multiple genes that function in a common pathway, thereby explaining the shared clinical phenotype. For example, FA, a bone marrow failure syndrome characterized by hypoplasia of all blood cell precursors (aplastic anemia), cancer predisposition, and abnormalities in organogenesis, is caused by mutations in at least 15 distinct genes that interact to sense and repair DNA cross-links (15). Indeed, verifying that candidate proteins function in this DNA repair pathway has strengthened the identification of new FA genes. Analogously, it is predicted that new DBA genes will somehow participate in ribosome biology. This raises the interesting question of whether ribosomes and GATA-1 are functionally linked. Both DBA and loss of GATA-1 induce apoptosis of erythroid precursors (16, 17). Through direct and indirect transcriptional actions, GATA-1 inhibits the expression of proapoptotic proteins and promotes the expression of antiapoptotic ones (18). Moreover GATA-1 binds p53 directly to inhibit its apoptotic activities (19). Thus, GATA-1 and ribosome biosynthesis may intersect through their abilities to control erythroid apoptotic regulators. In addition, ribosome dysfunction could selectively affect the translation of specific mRNAs, altering the proteome with particularly deleterious consequences in erythroid cells. Through this mechanism, it is possible that mutations in RP subunit genes somehow impair the expression of GATA-1 and/or its cofactors. Alternatively, it is possible that GATA-1 and ribosome functions are not directly linked and that two independent pathways cause the same phenotype. Other inherited disorders, for example hereditary deafness, retinitis pigmentosa, and VACTERL/VATER association, are genetically heterogeneous, each with causative mutations in genes affecting diverse functional pathways. Complicating the issue, similar or identical GATA1 mutations can produce varying clinical manifestations in different individuals (Figure 3), explaining in part why the patients described by Sankaran et al. were diagnosed with DBA, whereas the family described by Hollanda et al. carries the diagnosis of “congenital anemia with trilineage dysplasia” (13).