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X Chromosome-Linked and Mitochondrial Gene Control of Leber Proc. Nati. Acad. Sci. USA Vol. 88, pp. 8198-8202, September 1991 Genetics X chromosome-linked and mitochondrial gene control of Leber hereditary optic neuropathy: Evidence from segregation analysis for dependence on X chromosome inactivation (two-locus inheritance/cytoplasmic inheritance/reduced penetrance) XIANGDONG BU AND JEROME I. ROTTER* Medical Genetics Birth Defects Center, Departments of Medicine and Pediatrics, Cedars-Sinai Medical Center and University of California School of Medicine, Los Angeles, CA 90048 Communicated by Giuseppe Attardi, July 1, 1991 ABSTRACT Leber hereditary optic neuropathy (LHON) linkage analysis, Chen et al. (5) excluded an X-linked gene has been shown to involve mutation(s) of mitochondrial DNA, alone as the cause for LHON. Earlier, Imai and Moriwaki (6) yet there remain several confusing aspects of Its inheritance not advanced the theory of cytoplasmic inheritance. The identi- explained by mitochondrial inheritance alone, including male fication of a mtDNA point mutation for LHON by Wallace et predominance, reduced penetrance, and a later age of onset in al. (3) and Singh et al. (4) subsequently proved the decades- females. By extending segregation analysis methods to disor- old hypothesis regarding the cytoplasmic inheritance of ders that involve both a mitochondrial and a nuclear gene LHON (6). As mentioned above, however, a mitochondrial locus, we show that the available pedigree data for LHON are mutation alone still cannot explain many ofthe features ofthe most consistent with a two-locus disorder, with one responsible transmission pattern of LHON, including the strong male gene being mitochondrial and the other nuclear and X chro- bias and the reduced penetrance of LHON in the maternal mosome-linked. Furthermore, we have been able to extend the line pedigree. These features, together with the conspicuous two-locus analytic method and demonstrate that a proportion tissue-specific expression of LHON, suggest the involve- of affected females are likely heterozygous at the X chromo- ment of nuclear gene(s), presumably an X-linked gene. Wal- some-linked locus and are affected due to unfortunate X lace (7) has proposed a nuclear-cytoplasmic interaction hy- chromosome inactivation, thus providing an explanation for pothesis. However, even the proposal of both X-linked and the later age of onset in females. The estimated penetrance for mitochondrial gene mutations does not fully explain the a heterozygous female is 0.11 ± 0.02. The calculated frequency inheritance of LHON. Under an X-linked recessive and of the X chromosome-linked gene for LHON is 0.08. Among mitochondrial model, all male offspring ofan affected mother affected females, 60% are expected to be heterozygous, and the should be affected. If the nuclear gene is X-linked dominant, remainder are expected to be homozygous at the responsible X there should be more affected females than affected males. chromosome-linked locus. Both of these conflict with the actual observations. It has been further proposed by Wallace in 1987 (7) that differential expression in males could reflect the difference in X chro- Leber hereditary optic neuropathy (LHON), first described mosome number in males and females if this nuclear gene by Leber in 1871, is maternally transmitted and associated escapes X inactivation. We propose here the hypothesis that with acute and subacute visual loss in both young adult males it is X inactivation of a small number of embryonic precursor and females. The age of onset is the early 20s, and it is an cells for the optic tissue that can resolve the transmission average 2-15 years later for females than for males (refs. 1 pattern for LHON, and we support this hypothesis by a and 2; M. L. Savontaus, personal communication). The formal analysis of a large number of LHON pedigrees. visual loss, usually permanent and bilateral, is caused by By the theory of X chromosome inactivation, a heterozy- optic atrophy and large centrocecal scotomata. LHON has gous female's clinical phenotype will be dependent on the been shown to commonly involve a mitochondrial DNA combined effect ofeach individual cell ofthe involved tissue. (mtDNA) point mutation (3, 4), which explained the maternal The phenotype of each individual cell is determined by transmission pattern. Yet there remain several confusing whether the normal or abnormal X chromosome is active. aspects of its inheritance, which cannot be explained by Thus one heterozygous genotype corresponds to two differ- mitochondrial inheritance alone. These include male predom- ent phenotypes-affected or unaffected. This leads to poten- inance (a mitochondrial disorder should have 1:1 sex ratio), tial difficulties in linkage studies as regards the correct reduced penetrance (i.e., clearly unaffected females trans- classification of a heterozygous female. However, even with mitting the disease), later age of onset for females, and these difficulties, Vilkki et al. (8) have recently reported a expression limited to optic tissue. In this paper, we propose linkage study indicating that a nuclear gene determining the a two-locus mitochondrial and X chromosome-linked nuclear clinical manifestation of LHON is localized to the region of gene model that, taking X chromosome inactivation into proximal Xp. account, provides an explanation for these intriguing features A particularly interesting aspect of mitochondrial genetics of LHON inheritance. is that some peptide subunits are encoded by mtDNA and About 85% of LHON patients are male (1). In the early other proteins are encoded by nuclear DNA. Given the fact stage of research on the segregation pattern of LHON, an of nucleus-mitochondria interaction (9), it could be inferred X-linked mode of inheritance was proposed on the basis of that some mitochondrial disorders are due to deleterious this male predominance. However, this mode of inheritance interactions between the two genomes. Herein we have failed to explain the lack of transmission of the disease through males (i.e., to their daughters). On the basis of Abbreviations: mtDNA, mitochondrial DNA; LHON, Leber hered- itary optic neuropathy. The publication costs of this article were defrayed in part by page charge *To whom reprint requests should be addressed at: Division of payment. This article must therefore be hereby marked "advertisement" Medical Genetics (SSB-3), Cedars-Sinai Medical Center, 8700 W. in accordance with 18 U.S.C. §1734 solely to indicate this fact. Beverly Boulevard, Los Angeles, CA 90048. 8198 Downloaded by guest on September 29, 2021 Genetics: Bu and Rotter Proc. Natl. Acad. Sci. USA 88 (1991) 8199 modified our two-locus mitochondrial and nuclear gene mod- binomial except for omission of the class with no affected els (10) by incorporating the random inactivation of the X males, and thus is a truncated distribution. This selection chromosome. We show here that extending this analysis to method is thus equivalent to truncate selection. To account the LHON case can fully account for the unique transmission for the ascertainment bias introduced here, a correction was pattern observed in this disease. made in estimating the segregation ratio and the expected number ofthe affected and unaffected male offspring (18-21). METHODS To examine this hypothesis ofX inactivation at the nuclear locus, we then analyzed the aggregation of LHON in the Family Data. Our goal was to test the hypothesis that the female population of these data sets. Our model stated that clinical aggregation of disease in LHON families is due to there are two ways in which a female can be affected- (i) that simultaneous involvement of two loci, one mitochondrial and she is homozygous at the X-linked locus and (ii) that she is one X-linked. Three published pedigree data sets were used heterozygous but has undergone unfortunate X inactivation in this analysis. An individual with optic atrophy was defined with a predominant number of cells with the abnormal X as affected in all three data sets. We included in our segre- chromosome active in the optic tissue. gation analysis only the maternal line members whose age at Let q be the frequency of the abnormal X-linked gene (a) examination or age at death was beyond the mean age of for LHON, and K the probability of a heterozygous female onset of the disease, or who were not part of the youngest being affected-i.e., the penetrance. The probability of a generation in the pedigree if information on age was not female offspring being affected with LHON from the mating available. In this manner, we minimized the sampling error that would otherwise result from between a heterozygous female and a random male will be including those clinically defined as the segregation ratio T. T therefore is the sum of unaffected individuals who might become affected at a later the probability that the female offspring is homozygous age. affected at the X-linked locus Data set one contained four Finnish pedigrees (8, 11). All (q/2), plus the probability that four pedigrees shared the same mitochondrial mutation a female offspring is heterozygous (i.e., 1/2) times the prob- (causing LHON disease) and showed no evidence of hetero- ability for a heterozygous female to be affected (K). Thus for this plasmy mutation. The details of the pedigree struc- T = q/2 + K/2. tures were further clarified by direct communication with the [Il authors of refs. 8 and 11. A heterozygous female will be affected with LHON when the Data set two included Seedorffs 20 pedigrees from Den- proportion of affected cells in her optic tissues exceeds a mark (2, 12-14). Among them, pedigree A comprised nine certain limit. We define this limit as the disease threshold for generations and 254 maternal line individuals, and pedigree C the heterozygous female, which is dependent on the param- comprised eight generations and 124 members. eter K. The higher that K is, the lower the disease threshold.
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