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Rare Disease Genes—Lessons and Challenges Leena Peltonen1 and Annukka Uusitalo

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Rare Disease Genes—Lessons and Challenges Leena Peltonen1 and Annukka Uusitalo Downloaded from genome.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Insight/Outlook Rare Disease Genes—Lessons and Challenges Leena Peltonen1 and Annukka Uusitalo Department of Human Molecular Genetics, National Public Health Institute and Institute of Biomedicine, University of Helsinki, FIN-00300 Helsinki, Finland The fiercest competition in the field the history of affected individuals, ground. The strategy of using only a few of human genetics takes place in the which suggests that there is one major DNA samples has been highly successful area of genetic diseases that are common ancestor mutation. This situation allows in the locus identification of many rare at the population level—this is primarily the adoption of unique strategies to diseases (Nikali et al. 1995; van Soest et attributable to the potential commercial search for a causative locus: similarity al. 1996, this issue). utilization of emerging data. However, searches for the disease locus using DNA The phenomenon of shared alleles in dissection of the molecular background samples from just a few affected indi- affected individuals or significant devia- of many extremely rare diseases has viduals and searches for shared alleles or tion in the allelic frequencies of poly- proven to be highly useful for the de- homozygosity of genotypes. Using this morphic markers in disease chromo- tailed characterization of cellular dys- approach, an initial genome scan with somes compared to control chromo- function and the identification of novel 400 markers can be carried out in just a somes is called linkage disequilibrium. metabolic pathways, broadening our few days as compared to the weeks or This is sometimes observed with mark- understanding of biological processes in months required for genotyping all fam- ers over amazingly wide intervals, as ex- general. This information has largely ily members in traditional genome scans emplified in Table 1, which summarizes been obtained from research carried out using linkage analysis in diseases that the data on Finnish disease alleles. The in populations with exceptional enrich- have a more diverse mutational back- existence of linkage disequilibrium over ment of a given disease (Fig. 1). Although the global prevalence of rare diseases is insignificant [e.g., world- wide there are <200 known cases of pa- tients with infantile-type neuronal ce- roid lipofuscinosis (INCL) in compari- son to a global population prevalence of 1:65 for the recessive cystic fibrosis mu- tation or 1:8000 for dominant Marfan syndrome], this rarity does not necessar- ily reflect the impact of these diseases on biological research. From Population Sample to Gene Identification: Special Statistical Strategies Rare diseases are characteristically en- riched in populations that have been isolated for religious, linguistic or geo- graphical reasons; good examples of this are the Ashkenazi Jews or the Finns. From the viewpoint of population ge- netics, rare diseases have initially led to the identification of many population bottlenecks and have produced quite precise data on the time period at which the mutation was actually introduced Figure 1 The identification of a disease mutation is considered beneficial, as it provides tools into the population, thus providing ini- for assessing the pathogenic mechanisms of the disease and ultimately designing prevention tial clues to the genetic history of hu- and therapy. Research into the molecular background of many rare disorders has also provided man populations. Often a common an- the scientific community with various new strategies for the locus identification of a disease cestor or inbreeding can be verified in gene, as well as given new insight into metabolic pathways and biological processes. 7:765–767 ©1997 by Cold Spring Harbor Laboratory Press ISSN 1054-9803/97 $5.00 GENOME RESEARCH 765 Downloaded from genome.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Insight/Outlook al. 1994). Similarly, the finding that the Table 1. Interval Showing the Linkage Disequilibrium in the causative gene for the lethal infantile Disease Alleles of Finnish Disease Heritage brain disorder INCL encoded a palmi- Interval toyl protein thioesterase demonstrated Disease Gene location (cM) for the first time that proper removal of palmitoyl residues from lipid-modified Autoimmune polyendocrinopathy–candidiasis– 21q22.3 3 proteins is an absolute requirement for ectodermal dystrophy (APECED) the normal development and matura- Cartilage-hair hypoplasia (CHH) 9p21–p13 3 tion of neocortical neurons (Vesa et al. Choroideremia Xq21 9 1995). INCL is characterized by the rapid Congenital chloride diarrhoea (CCD) 7q31 13 death of cortical neurons, whereas neu- Congenital nephrosis (CNF) 19q12–q13.1 3 rons in lower parts of the CNS remain Cornea plana congenita 12q21 2.5 intact. Although details of both diastro- Diastrophic dysplasia (DTD) 5q31–q34 2 phic dysplasia and INCL remain to be Familial amyloidosis, Finnish type (FAF) 9q33 3.5 characterized further, these findings Infantile neuronal ceroid-lipofuscinosis (INCL) 1p32 2.5 have opened new avenues for research Infantile onset spinocerebellar ataxia (IOSCA) 10q23.3–q24.1 5 of the metabolism of both sulfate and Northern epilepsy (Kainuu epilepsy) 8ptel. 10 palmitoyl residues in specific cell types Progressive myoclonus epilepsy (PME) 21q22 5 and tissues. Retinoschisis Xp22.2–p22.1 10 A lysosomal enzyme deficiency, as- Salladisease 6q14–q15 10 partylglucosaminuria (AGU), resulting Usher syndrome, type III (USH3) 3q21–q25 7.5 in progressive mental retardation, serves Variant form of late infantile NCL (vLINCL) 13q21.1–q32 11 as a good example of a very rare disease that might initially be regarded as rather For original references, see Peltonen et al. (1995). uninteresting. However, years of inten- sive research into the pathogenesis of AGU exposed molecular details of more general relevance. At first, the need for elucidation of the disease mechanism such broad intervals suggests that ge- with the incomplete penetrance of hy- stimulated research into the defective nome-wide association-based analyses— pothetical disease gene(s). Monitoring enzyme, aspartylglucosaminidase perhaps not well-justified in mixed, het- of linkage disequilibrium in population (AGA), which had so far been hampered erogeneous populations—could also be isolates ought to be a highly powerful by failure to purify the protein to suffi- successful for locus searches in complex tool for the more precise localization of cient homogeneity because of its low polygenic diseases in genetic isolates predisposing genes. However, the situa- quantity in tissues. Following identifica- (Lander and Schork 1994). tion in complex diseases is likely to be tion of the gene and the major disease- The linkage disequilibrium-based more problematic than in the case of causing mutation, in vitro expression strategy has also been utilized success- rare disease alleles because of the ex- studies of normal and mutated AGA fully to restrict the critical DNA region pected high population prevalence and polypeptides clarified the details of its after initial assignment of the disease lo- multiplicity of predisposing muta- biosynthesis and intracellular process- cus. This is perhaps best exemplified in tions—even in an isolate. ing and provided clues to some general the isolation of the gene defective in a features of the cell biology of lysosomal severe cartilage disorder called diastro- enzymes (Ikonen et al. 1991a,b, 1993; Shortcuts to Gene Functions phic dysplasia. Utilizing the rules of bac- Mononen et al. 1993; Riikonen et al. and Clues to Essential terial genetics (Luria and Delbru¨ck 1943) 1994, 1996). Subsequent crystallization Biological Pathways and a simplified population genetic data on the AGA enzyme revealed a model based on the assumption of a Well-characterized tissue symptoms in novel catalytic mechanism based on the small number of ancestors in the Finn- patients with rare diseases provide im- amino-terminal nucleophile and indi- ish population, the gene was originally mediate understanding of the function cated that AGA is the first eukaryotic predicted to be located 64 kb from the and tissue expression of the identified member of a new enzyme family of ami- polymorphic marker showing the stron- disease gene. On many occasions, to- dohydrolases (Oinonen et al. 1995; Tik- gest linkage disequilibrium. When the tally new metabolic pathways have ei- kanen et al. 1996a,b). Structural analyses gene, which encodes a sulfate trans- ther been identified or associated for the also provided the means for characteriz- porter protein, was isolated, it was 70 kb first time with a specific cell type or de- ing the lysosomal targeting process of from this marker (Ha¨stbacka et al. 1994). velopmental stage. Again, some Finnish AGA in detail and increased our compre- Again, applications of this method for diseases exemplify this: The identifica- hension of the targeting of lysosomal complex diseases and their predisposing tion of the mutated gene for diastrophic enzymes in general (R. Tikkanen, M. Pel- genes are obvious. Characteristically the dysplasia provided evidence of the ex- tola, C. Oinonen, J. Rouvinen, and L. DNA region identified to be associated ceptional sensitivity of cartilage cells to Peltonen, in prep.). with a common trait is very wide be- the relative lack of sulfate ions as com- From a purely biological standpoint, cause of statistical problems combined pared to other cell types (Ha¨stbacka et the study of rare diseases has potential 766 GENOME RESEARCH Downloaded from genome.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Insight/Outlook similar to research with knockout mice, Ikonen, E., N. Enomaa, I. Ulmanen, and L. which have been used traditionally for Peltonen. 1991b. Genomics 11: 206–211. characterizing the tissue consequences of a gene defect. The phenotype of these Ikonen, E., I. Julkunen, O.-K. Tollersrud, N. Kalkkinen, and L. Peltonen. 1993. EMBO J. rare diseases is extremely well described, 12: 295–302. and despite the complexity and indi- vidual variability of the genetic back- Lander, E.S. and N.J.
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