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Mutations in Fibroblast Growth-Factor Receptor 3 in Sporadic Cases of Achondroplasia Occur Exclusively on the Paternally Derived Chromosome  Douglas J.

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Presentation on theme: "Mutations in Fibroblast Growth-Factor Receptor 3 in Sporadic Cases of Achondroplasia Occur Exclusively on the Paternally Derived Chromosome  Douglas J."— Presentation transcript:

1 Mutations in Fibroblast Growth-Factor Receptor 3 in Sporadic Cases of Achondroplasia Occur Exclusively on the Paternally Derived Chromosome  Douglas J. Wilkin, Jinny K. Szabo, Rhoda Cameron, Shirley Henderson, Gary A. Bellus, Michelle L. Mack, Ilkka Kaitila, John Loughlin, Arnold Munnich, Bryan Sykes, Jacky Bonaventure, Clair A. Francomano  The American Journal of Human Genetics  Volume 63, Issue 3, Pages (September 1998) DOI: /302000 Copyright © 1998 The American Society of Human Genetics Terms and Conditions

2 Figure 1 FGFR3 achondroplasia mutant and wild-type allele-specific oligonucleotide primers, designed to create a mismatch at the nucleotide adjacent to the 3′ nucleotide, with the 3′ nucleotide corresponding to FGFR3 nucleotide 1138, the base mutated in the common achondroplasia mutation analyzed in this study. The normal-allele PCR primers (1138wt-F and 1138wt-R) contained the wild-type nucleotide G (or C on the reverse primer) as the 3′ base, maximizing the mismatch with the mutant allele. The mutant-allele PCR primers (1138mut-F and 1138mut-R) contain the achondroplasia-mutation nucleotide A (or T on the reverse primer) as the 3′ base, maximizing the mismatch with the normal allele. The American Journal of Human Genetics  , DOI: ( /302000) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

3 Figure 2 PmlI (A) and PflMI (B) restriction digestion of allele-specific PCR products, as recommended by the manufacturer. The sizes of products of restriction digestion are shown. Analyses of four families are presented. Allele-specific PCR of genomic DNA was performed with either a normal-sequence (wt) oligonucleotide primer or an oligonucleotide primer specific for the common achondroplasia mutation (mut) (see fig. 1). The allele-specific primer used in the PCR reactions is depicted as wt or mut. Reactions using DNA from the probands are shown in lanes 2, 3, 6, and 7. PCR using genomic DNA from the affected child was performed with either a wt oligonucleotide primer or a mut primer. Parental DNAs are shown in lanes 1, 4, 5, and 8. PCR of parental genomic DNA was performed with a wt primer. In each case shown, the allele amplifying with the mut primer is inherited from the father. The American Journal of Human Genetics  , DOI: ( /302000) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

4 Figure 3 Potential paternal and maternal alleles. The PmlI polymorphism is used as an example. Allele-specific PCR was performed with the proband's genomic DNA, and digestion was performed with the appropriate restriction enzyme. If the proband was heterozygous for the polymorphism, the parental DNAs were analyzed. The possible parental alleles and the parent from whom the mutant allele would be inherited are shown. +/+ = Homozygosity for the polymorphic sequence, −/− = homozygosity for the normal sequence, and +/− = heterozygosity at the site. The American Journal of Human Genetics  , DOI: ( /302000) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

5 Figure 4 Analysis of 99 probands. A total of 21, 9, and 17 probands were heterozygous for the PmlI, PflMI, and poly(G) polymorphisms, respectively. From those heterozygous probands, respectively, 19, 6, and 15 parental alleles were informative for the determination of the parental origin of the achondroplasia allele. In all 40 informative families, the mutant allele was inherited from the father. The American Journal of Human Genetics  , DOI: ( /302000) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

6 Figure 5 Sequence analysis of FGFR3 intron 9 poly(G) polymorphism. Normal intron 9 sequence (A) contains a stretch of 11 consecutive guanosine residues, whereas the polymorphic sequence (B) has a G deletion in this sequence. The American Journal of Human Genetics  , DOI: ( /302000) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

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