ABCMdb

PMID: 11179012

Ringpfeil F, Nakano A, Uitto J, Pulkkinen L
Compound heterozygosity for a recurrent 16.5-kb Alu-mediated deletion mutation and single-base-pair substitutions in the ABCC6 gene results in pseudoxanthoma elasticum.
Am J Hum Genet. 2001 Mar;68(3):642-52. Epub 2001 Feb 9., [PubMed]

Sentences

No. Mutations Sentence Comment

24 ABCC6 p.Arg1141* ABCC6 p.Arg1164* ABCC6 p.Arg1164* OF AFFECTED FAMILY MEMBERS COMPLEMENTARY MUTATION PHENOTYPE a When Studied At Disease Onset 1 (German) 61 9 2 R1164X Skin-cobblestoning on neck, antecubital fossae, and wrists, sagging skin in axillae and bilateral groin; eyes-angioid streaks, central vision loss; CVS-claudication, ischemic attack; other-ovarian cancer 2 (British) 60 Unknown 3 R1164X Skin-moderate to severe involvement; eyes-loss of vision 3 (British) 41 Unknown 3 R1141X Skin-cobblestoning on neck, axillae, and bilateral groin; eyes-angioid streaks; CVS-coronary artery disease, GI bleeding 4 (Greek) 60 51 2 3736-1GrA Skin-cobblestoning in axillae, bilateral groin, and antecubital fossae; eyes-angioid streaks, central vision loss, macular degeneration; CVS-angina, abdominal pain, loss of peripheral pulses; other-depression, chronic fatigue syndrome a CVS p cardiovascular system; GI p gastrointestinal. Login to comment 43 ABCC6 p.Arg1164* Haplotype analysis with 12 microsatellite markers (left side) spanning ~9 cM of 16p13.1 allowed assignment of phase of a deletion mutation (D) and a nonsense mutation (R1164X), as indicated at the bottom of the haplotypes. Login to comment 56 ABCC6 p.Arg1141* ABCC6 p.Arg1164* Clinical Assessment of Families with PXE Members of families 1, 3, and 4 were personally examined at least by one of the authors; information on Table 2 Haplotypes of Affected Individuals in Four Unrelated Families with PXE MARKER a HAPLOTYPE FOR b del/R1164X del/R1141X; Family 3 del/3736-1GrA; Family 4Family 1 Family 2 D16S3114 4 4 10 5 9 6 9 4 D16S500 6 3 4 10 4 8 6 10 D16S2619 2 1 3 2 2 3 2 2 D16S3079 2 3 2 3 1 9 8 7 D16S3060 4 2 8 2 7 4 5 8 D16S405 8 3 4 3 4 8 3 4 D16B9622 2 2 2 2 1 2 3 1 D16S764 4 2 3 2 2 2 3 2 D16S79 8 0 3 3 3 3 3 2 D16S3103 7 1 3 1 9 3 7 4 D16S3017 3 2 4 1 5 4 2 4 D16S499 1 5 5 1 8 7 5 8 D16S3036 8 8 7 7 8 11 4 6 a The distances between the listed markers are as follows: telomere, D16S3114 (1.9 cM) D16S500 (0.5 cM) D16S2619 (0.7 cM) D16S3079 (0.5 cM) D16S3060 (22 kb) D16S405 (430 kb) D16B9622 (0.7 kb) ABCC6 (317 kb) D16S764 (8 kb) D16S79 (1.5 cM) D16S3103 (0.4 cM) D16S3017 (0.9 cM) D16S499 (1.5 cM) D16S3036, centromere. Login to comment 59 ABCC6 p.Arg1164* The shared haplotype in alleles containing the R1164X mutation in families 1 and 2 is in boldface italics. Login to comment 70 ABCC6 p.Arg1164* Comparative sequencing of the proband`s PCR product revealed an apparently homozygous single-base-pair substitution, 3490CrT, which resulted in replacement of a codon for arginine by a stop codon, a mutation designated "R1164X" (fig. 2A). Login to comment 72 ABCC6 p.Arg1164* CSGE and sequence analysis of other members of this family indicated that the older, clinically affected brother (II-2) of the proband similarly appeared homozygous for the mutation R1164X. Login to comment 74 ABCC6 p.Arg1164* The proband`s maternal aunt (I-10) and paternal uncle (I-1) showed the normal allele only, whereas the proband`s younger brother (II-7) was clearly heterozygous for the mutation R1164X. Login to comment 75 ABCC6 p.Arg1164* Sequence analysis of the children (generation III) of the two affected individuals revealed that five of them were heterozygous for the mutation R1164X, whereas two of them (III-2 and III-8) were apparently homozygous for the normal sequence. Login to comment 78 ABCC6 p.Arg1164* The inheritance of the latter allele conferred heterozygous carrier status of the mutation R1164X to individuals II-7, III-1, III-4, III-5, III-7, and III-9 (fig. 1). Login to comment 80 ABCC6 p.Arg1164* Collectively, these findings suggest that the proband (II-5) and her clinically affected older brother (II-2) had inherited from their father a nonsense mutation R1164X in exon 24 of the ABCC6 gene, and they had inherited from their mother a deletion mutation spanning exon 24 of the gene, thus reducing the paternal nonsense mutation to hemizygosity. Login to comment 93 ABCC6 p.Arg1164* Initial mutation detection by PCR amplification of ABCC6, followed by CSGE and nucleotide sequencing, demonstrated the presence of an apparently homozygous R1164X mutation in both the proband and his older brother. Login to comment 95 ABCC6 p.Arg1164* Restriction-enzyme digestion with AciI revealed that, of the proband`s three children, the daughter and the younger son showed evidence for the wild-type allele only, while the middle child was clearly heterozygous for the R1164X mutation. Login to comment 96 ABCC6 p.Arg1164* The two children of the proband`s daughter, who were examined at the ages of 12 and 10 years, respectively, were clinically normal and did not show evidence for the R1164X mutation. Login to comment 97 ABCC6 p.Arg1164* If the proband were truly homozygous for the R1164X mutation, his children would be expected to be heterozygous carriers of this mutation. Login to comment 99 ABCC6 p.Arg1141* In these families, designated here as "family 3" (family 3 in Ringpfeil et al. 2000) and "family 4" (family 4 in Ringpfeil et al. 2000), a nonsense mutation (R1141X) and a splicing mutation (3736-1GrA) are located in exon 24 and in the 3 acceptor splice site of intron 26, respectively. Login to comment 146 ABCC6 p.Arg1164* The deletion mutation in each of these four families is associated with single-base-pair substitutions, two of them being the same one-R1164X in families 1 and 2. Login to comment 148 ABCC6 p.Arg1164* Thus, a founder effect for the R1164X mutation cannot be excluded with certainty, despite the apparently diverse ethnic backgrounds of these two families (table 1). Login to comment 154 ABCC6 p.Arg1141* ABCC6 p.Arg1164* ABCC6 p.Arg1164* In each family, the proband was initially shown to be apparently homozygous for a nucleotide substitution, resulting in either a nonsense mutation (R1164X, R1164X, and R1141X in families 1, 2, and 3, respectively) or a splice-site mutation (3736-1GrA in family 4). Login to comment 180 ABCC6 p.Arg1141* ABCC6 p.Arg1164* Exon 24 encodes a segment of MRP6 residing within TMSD3, and the mutations R1141X and R1164X are predicted to result in the synthesis of a truncated polypeptide entirely devoid of NBF2 (fig. 4A). Login to comment 214 ABCC6 p.Arg1268Gln Proc Natl Acad Sci USA 90:10325-10329 Germain DP, Perdu J, Remones V, Jeunemaitre X (2000) Homozygosity for the R1268Q mutation in MRP6, the pseudoxanthoma elasticum gene, is not disease-causing. Login to comment