A Missense Mutation in a Highly Conserved Region of CASQ2 Is Associated with Autosomal Recessive Catecholamine-Induced Polymorphic Ventricular Tachycardia.

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A Missense Mutation in a Highly Conserved Region of CASQ2 Is Associated with Autosomal Recessive Catecholamine-Induced Polymorphic Ventricular Tachycardia in Bedouin Families from Israel Hadas Lahat, Elon Pras, Tsviya Olender, Nili Avidan, Edna Ben-Asher, Orna Man, Etgar Levy-Nissenbaum, Asad Khoury, Avraham Lorber, Boleslaw Goldman, Doron Lancet, Michael Eldar The American Journal of Human Genetics Volume 69, Issue 6, Pages 1378-1384 (December 2001) DOI: 10.1086/324565 Copyright © 2001 The American Society of Human Genetics Terms and Conditions

Figure 1 a, Baseline EKG strip (lead 3) in a patient showing normal sinus rhythm. b, EKG strip (lead 3) in the same patient during an exercise test, showing sustained PVT. The American Journal of Human Genetics 2001 69, 1378-1384DOI: (10.1086/324565) Copyright © 2001 The American Society of Human Genetics Terms and Conditions

Figure 2 a, Physical map of the PVT locus. Landmark genes are shown as red boxes with their HUGO nomenclature symbols. Microsatellite markers are indicated by arrows (↓) pointing to their exact position on the genomic bar map. Black denotes the boundaries of the linkage interval defined elsewhere (Lahat et al. 2001), and green indicates markers within the linkage interval defined in the present study. b, Expanded view of a 75-kb segment, showing the genomic organization of the CASQ2 interval. The interval is covered by two genomic clones that have 5-kb overlap. AL449264 contains the first four exons, and AL450389 contains the other seven exons, depicted by blue boxes. The lengths of the exons are shown below the boxes, and those of the introns are shown above the line. The translation-initiation site and the stop codon are indicated. The American Journal of Human Genetics 2001 69, 1378-1384DOI: (10.1086/324565) Copyright © 2001 The American Society of Human Genetics Terms and Conditions

Figure 3 a, Sequence chromatograms from a patient (M/M), a noncarrier (WT/WT), and a carrier (WT/M). There is a G→C substitution at nucleotide 1038 in exon 9, converting aspartic acid to histidine at codon 307. b, BamHI restriction analysis of the D307H mutation in one of the Bedouin families. The 258-bp PCR product of exon 9 is cleaved in the carrier chromosome to yield 131-bp and 127-bp products that comigrate on the agarose gel. MW = molecular weight marker. The American Journal of Human Genetics 2001 69, 1378-1384DOI: (10.1086/324565) Copyright © 2001 The American Society of Human Genetics Terms and Conditions

Figure 4 a, Multiple alignment of a segment of the human CASQ2 protein with the corresponding segments in some of its homologues. The sequences were selected using a BLASTP (Altschul et al. 1997; NCBI BLAST Home Page) search of human CASQ2 against the nonredundant protein database. Multiple alignment of the entire protein length was performed by the ClustalW program, using the default parameters (Higgins et al. 1996). Acidic amino acids are shown in red, basic amino acids in blue, and yellow denotes all other amino acids. The top sequence is for the mutated human CASQ2, and the arrow (↓) indicates the D307H mutated position. The GenBank accession numbers of the aligned proteins are as follows: human cardiac calsequestrin (CASQ2), O14958; mouse cardiac calsequestrin (CASQ2), O09161; human skeletal muscle calsequestrin (CASQ1), P31415; chicken skeletal muscle calsequestrin (CASQ1), P19204; frog skeletal muscle calsequestrin (CASQ1), P31231; Caenorhabditis elegans calsequestrin, Q20203; and Drosophila melanogaster disulfide isomerase, gi|1709616. This is the Drosophila protein showing highest protein similarity to human CASQ2, and both share a thiorodoxin-like structural motif. b, Ribbon drawing of human CASQ2 three-dimensional homology model. The D307 amino acid is shown in orange. The model was calculated using “homology” and “discovery” modules of Biosym/MSI. The protein termini were omitted for the modeling calculation, leaving a G22-to-L366 amino acid core. The default parameters were used to generate a loop (E345 to P353). Energy minimization was performed using steepest-descent (100 iterations) and conjugate-gradient (1,000 iterations) algorithms. c, A closer look at the mutant position domain. The basic and acidic amino acids are shown, in blue and red, respectively, as “balls and sticks.” The top model is of the wild-type protein (D307), and the bottom model is of the mutant protein (H307). The substitute position is shown in orange (for D307) and green (for H307). The histidine in the mutant form appears to disrupt a band of negative amino acids and could thus upset the protein’s charge balance. The American Journal of Human Genetics 2001 69, 1378-1384DOI: (10.1086/324565) Copyright © 2001 The American Society of Human Genetics Terms and Conditions