Double Heterozygosity for a RET Substitution Interfering with Splicing and an EDNRB Missense Mutation in Hirschsprung Disease Alberto Auricchio, Paola.

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Double Heterozygosity for a RET Substitution Interfering with Splicing and an EDNRB Missense Mutation in Hirschsprung Disease Alberto Auricchio, Paola Griseri, Maria Luisa Carpentieri, Nicola Betsos, Annamaria Staiano, Arturo Tozzi, Manuela Priolo, Helen Thompson, Renata Bocciardi, Giovanni Romeo, Andrea Ballabio, Isabella Ceccherini The American Journal of Human Genetics Volume 64, Issue 4, Pages 1216-1221 (April 1999) DOI: 10.1086/302329 Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 1 SSCP analysis of the RET exon 11 transcript from affected individuals carrying the I647I silent mutation. PCR products corresponding to this exon from father, mother, and patient 1 genomic DNA are represented in lanes 1, 2, and 3, whereas lanes 4, 5, and 6 show the PCR products obtained from the cDNA of patients 1 and 2 and a control individual, respectively. Note that the shifted upper band corresponding to the mutated allele present in lanes 2 and 3 is absent in the cDNAs of patients 1 and 2 (lanes 4 and 5), which show only the normal allele present in the cDNA from a control individual (lane 6). The American Journal of Human Genetics 1999 64, 1216-1221DOI: (10.1086/302329) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 2 ARMS analysis of the RET exon 11 from patient 2 genomic DNA and cDNA. PCR products were obtained by use of oligonucleotide primers specific for either the normal (lanes 1 and 3) or the I647I (lanes 2 and 4) RET alleles. A band of the expected size is amplified from patient genomic DNA with both sets of primers (lanes 1 and 2), whereas at the cDNA level the normal (lane 3), but not the mutated, allele (lane 4) is present. The American Journal of Human Genetics 1999 64, 1216-1221DOI: (10.1086/302329) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 3 In vitro analysis of the RET exons 10 and 11 splicing products from both the normal and the I647I mutated alleles (see text for details). a, Schematic representation of the RET constructs used for the in vitro splicing analysis. b, RT-PCR amplification using primers designed in exons 10 and 11, as indicated in a, from total RNA of COS-7 cells transiently transfected with the RET wild-type (lane 1) and the I647I (lane 2) constructs. Note the abnormal products present in lane 2. c, Sequence analysis of the 255-bp products from lanes 1 and 2 shown in b corresponded to the normal and mutated RET alleles, respectively, an observation consistent with the use of canonical “gt” and “ag” donor and acceptor splice sites (underlined in the partial intronic sequence given in lowercase letters). Conversely, sequence analysis of the 148-bp and 120-bp products revealed two exon 11 deleted forms resulting from the use of cryptic acceptor “ag” sites activated to generate the two abnormal products (underlined in the sequence of the 5′ portion of exon 11 given in capital letters). The two alternative nucleotides involved in the neutral substitution of codon 647 (T in the normal allele and C in the variant allele) are shown in boldface type. The American Journal of Human Genetics 1999 64, 1216-1221DOI: (10.1086/302329) Copyright © 1999 The American Society of Human Genetics Terms and Conditions