Ancient Missense Mutations in a New Member of the RoRet Gene Family Are Likely to Cause Familial Mediterranean Fever The International FMF Consortium

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Ancient Missense Mutations in a New Member of the RoRet Gene Family Are Likely to Cause Familial Mediterranean Fever The International FMF Consortium Cell Volume 90, Issue 4, Pages 797-807 (August 1997) DOI: 10.1016/S0092-8674(00)80539-5

Figure 1 Schematic Representation of the MEFV Region on Chromosome 16p13.3 (A) ∼1 Mb region over which a cosmid contig was constructed (Sood et al. 1997). PKD1, polycystic kidney disease 1; TSC2, tuberous sclerosis 2; RSTS, Rubinstein-Taybi syndrome; CREBBP, CREB binding protein gene. (B) ∼285 kb candidate interval defined by intrafamilial recombination events in our panel of families (Balow et al. 1997). D16S3405–D16S3373 is the minimal candidate interval defined by historical recombinants in the present study. (C) Representation of the genomic structure of the v75-1 gene. Shaded boxes represent exons; introns are drawn to scale. Numbers above the boxes represent the size of the exons, in bp. Numbers below the boxes reflect the order of the exons, with (1) being the most 5′. Cell 1997 90, 797-807DOI: (10.1016/S0092-8674(00)80539-5)

Figure 2 The Predicted Protein Sequence Encoded by cDNA v75-1 The boxed segment from aa 266 to 280 is a bZIP transcription factor basic domain; the boxed segment from aa 420 to 437 is a Robbins/Dingwall consensus nuclear targeting signal. The segment indicated by plus signs between residues 375 and 407 is a potential B-box zinc finger domain. The region double-boxed from residue 577 to 757 is a rfp, or B30.2, domain. Within this box, the three mutated amino acids are double-underlined. Cell 1997 90, 797-807DOI: (10.1016/S0092-8674(00)80539-5)

Figure 3 Expression Profile of the v75-1 Gene (A) Results of hybridization of a probe derived from exon 2 on multiple-tissue Northern blots. A transcript of 3.7 kb is present in peripheral blood leukocytes and colorectal adenocarcinoma SW480. HL-60, promyelocytic leukemia; K-562, erythroleukemia; MOLT4, lymphoblastic leukemia; A549, lung carcinoma; G361, melanoma. (B) Hybridization of the same exon 2 probe on Northern blot with mRNA from purified PMNs and lymphocytes. PMN lanes represent preparations from different individuals. A β-actin control is shown below. Cell 1997 90, 797-807DOI: (10.1016/S0092-8674(00)80539-5)

Figure 4 DNA Sequence Electropherograms Demonstrating the M680I, M694V, and V726A Substitutions For each mutation, individuals who are homozygous for the normal allele are shown at the top, heterozygotes between the normal and mutant allele are shown in the middle, and homozygotes for the mutation are shown at the bottom. On the pedigree diagram, the heterozygote is shown as an open red symbol, and the homozygote for the mutation is shown as a closed red symbol. The control for the M680I mutation is individual 76-06, the control for M694V is 76-02, and the control for V726A is 3-01. Cell 1997 90, 797-807DOI: (10.1016/S0092-8674(00)80539-5)

Figure 5 Multiple Sequence Alignment of the C-Terminal End of Human Pyrin Sequences shown have statistical similarity as assessed by BLAST (Altschul et al. 1990). Search cutoffs used to identify homologs were a Karlin-Altschul score of two aligned sequences ⩾ 70 with a probability ⩽ 10−3. At each position, residues occurring in a majority of the sequences are shown in inverse type. The numbering scheme at the top of the figure is based on the sequence of pyrin. The positions of secondary structural elements in the wild-type pyrin (here, all β sheets) as predicted by the profile neural network method PHDsec (Rost and Sander 1993 Rost and Sander 1994) are shown as bold, horizontal arrows below the alignment. The residues altered in the three mutants are indicated by downward-pointed arrowheads above the alignment. hum-RFP, RET finger protein (SWISS-PROT P14373); xla-xnf7, nuclear phosphoprotein xnf7, Xenopus laevis (PIR A43906); pwa-A33, zinc-binding protein A33, Pleurodeles waltl (SWISS-PROT Q02084); hum-SS-A/Ro, 52 kDa RO protein (SWISS-PROT P19474); hum-afp, acid finger protein (GenBank U09825); hum-BT, butyrophilin (GenBank U90552); hum-efp, estrogen-responsive finger protein (PIR A49656); hum-B30-2, B30-2 gene, (PRF 2002339); pig-RFB30, ring finger protein RFB30, Sus scrofa (EMBL Z97403); hum-Staf-50, transcription regulator Staf-50 (PIR A57041). Cell 1997 90, 797-807DOI: (10.1016/S0092-8674(00)80539-5)