Retinitis Pigmentosa and Progressive Sensorineural Hearing Loss Caused by a C12258A Mutation in the Mitochondrial MTTS2 Gene Fiona C. Mansergh, Sophia.

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Retinitis Pigmentosa and Progressive Sensorineural Hearing Loss Caused by a C12258A Mutation in the Mitochondrial MTTS2 Gene Fiona C. Mansergh, Sophia Millington-Ward, Avril Kennan, Anna-Sophia Kiang, Marian Humphries, G. Jane Farrar, Peter Humphries, Paul F. Kenna The American Journal of Human Genetics Volume 64, Issue 4, Pages 971-985 (April 1999) DOI: 10.1086/302344 Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 1 Family ZMK. Individuals denoted by an asterisk (*) have been clinically assessed in detail and have donated DNA samples. The individual denoted by a question mark (?), V-18, is the affected granddaughter of an apparently unaffected individual (III-5). Generation numbers are given on the far left side, and numbers denoting individuals are given below the pedigree symbols. The American Journal of Human Genetics 1999 64, 971-985DOI: (10.1086/302344) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 2 Linkage map of microsatellite markers on chromosome 9. This map was created by CRI-MAP version 2.4 (Lander and Green 1987). Genotype data used to create this map were downloaded from the CEPH database and were merged with CEPH data from markers D9S118 and D9S121 obtained by us. Approximate positions of nonuniquely placed markers are given on the right: markers indistinguishable, by recombination, from just one other locus are placed beside the latter and are assumed to occupy roughly the same position; markers indistinguishable, by recombination, from a number of uniquely placed loci are indicated beside the arrows. Each arrow defines the interval between which the nonuniquely placed marker(s) beside and to the right of the pertinent arrow can be found. Male (McM), female (FcM) and sex-averaged cM values for the genetic distances between the uniquely placed markers are given on the far left side of the diagram. The American Journal of Human Genetics 1999 64, 971-985DOI: (10.1086/302344) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 3 Multipoint analysis of only the affected members of the pedigree, indicating that the disease gene in family ZMK is significantly excluded from the 9q region where there previously had been a suggestion of linkage. Markers that map exactly to the same position are immediately adjacent to one another and underlined. The American Journal of Human Genetics 1999 64, 971-985DOI: (10.1086/302344) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 4 Haplotypes on 9q in family ZMK. Note the transmission of different chromosome types through the pedigree; those shared by related individuals are depicted as shaded bars. No one haplotype is shared by all affected individuals. In addition, the two separate branches of the family do not appear to have in common any 9q portion between HXB and the telomere. The region of tightest linkage is between markers D9S260 and D9S121 inclusive. There are four recombinants with the disease locus in this region—namely, those in IV-16, IV-34, and V-14 and that between the two major branches of the family. Individuals IV-16, IV-34, and V-14 are consistently recombinant with the disease locus, right across the region examined. Two of these individuals have affected offspring, and V-14 is severely affected; he was legally blind at age 21 years. In addition, individual III-5 has an affected granddaughter, increasing to five the number of recombinants with the disease locus. The most likely explanation for these data is that the disease locus is not on 9q. The American Journal of Human Genetics 1999 64, 971-985DOI: (10.1086/302344) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 5 Sequence analysis of mtDNA samples from blood lymphocytes (A) and muscle (B) from affected individual IV-22 and from blood lymphocytes from an unaffected control (C). The C→A mutation at position 12258 (→) is present in both affected individuals and is absent in the unaffected control. The American Journal of Human Genetics 1999 64, 971-985DOI: (10.1086/302344) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 6 SSCPE analysis using PCR-amplified DNA from members of family ZMK. It is noteworthy that the wild-type (upper band) and mutant (lower band) mtDNA fragments can be distinguished. Both conformations of mtDNA are present in most affected individuals (e.g., see lanes 2, 5, and 8–10). However, some affected individuals have mtDNA that is mostly mutant. It is noteworthy that the wild-type:mutant mtDNA ratio in blood and muscle tissue varies significantly in individual IV-22 (lanes 2 and 3). The data indicate that there is no clearly evident correlation between the wild-type:mutant mtDNA ratio in blood and disease severity. The American Journal of Human Genetics 1999 64, 971-985DOI: (10.1086/302344) Copyright © 1999 The American Society of Human Genetics Terms and Conditions