Volume 87, Issue 3, Pages (November 1996)

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Volume 87, Issue 3, Pages 543-552 (November 1996) Familial Hemiplegic Migraine and Episodic Ataxia Type-2 Are Caused by Mutations in the Ca2+ Channel Gene CACNL1A4 Roel A Ophoff, Gisela M Terwindt, Monique N Vergouwe, Ronald van Eijk, Peter J Oefner, Susan M.G Hoffman, Jane E Lamerdin, Harvey W Mohrenweiser, Dennis E Bulman, Maurizio Ferrari, Joost Haan, Dick Lindhout, Gert-Jan B van Ommen, Marten H Hofker, Michel D Ferrari, Rune R Frants Cell Volume 87, Issue 3, Pages 543-552 (November 1996) DOI: 10.1016/S0092-8674(00)81373-2

Figure 1 Genetic Map, Cosmid Contig, and Global Exon Distribution of the CACNL1A4 Gene on Chromosome 19p13.1 Cosmid contig is shown with EcoRI restriction sites, available via Lawrence Livermore National Laboratory (LLNL); exon positions are indicated schematically, regardless of exon or intron sizes (Table 1). D19S1150 is a highly polymorphic intragenic (CA)n-repeat. Cell 1996 87, 543-552DOI: (10.1016/S0092-8674(00)81373-2)

Figure 2 Expression of Human P/Q-Type Calcium Channel α1-Subunit Gene (CACNL1A4) Tested in Different Tissues Northern blot of total RNA from rhesus monkey tissues (total brain, cerebellum, cortex, hypothalamus, muscle, heart, kidney, liver), human lymphocytes, and mouse skin, hybridized with human cDNA probe 1 (See cDNA Sequence section of Experimental Procedures). Size of transcript was estimated at 9.8 kb. Cell 1996 87, 543-552DOI: (10.1016/S0092-8674(00)81373-2)

Figure 3 Membrane Topology of α1 Subunit of the P/Q-Type Ca2+-Channel, CACNL1A4 The location and amino acid substitutions are indicated for mutations that cause familial hemiplegic migraine (FHM) and episodic ataxia type-2 (EA-2). Cell 1996 87, 543-552DOI: (10.1016/S0092-8674(00)81373-2)

Figure 4 Mutation Detection in the CACNL1A4 Gene in FHM Families Detection of four CACNL1A4 missense mutations in five different FHM families by restriction site (A, C, and D) or SSCP (B) analysis of PCR products. All missense mutations cosegregate with the disease within the families. Restriction site analysis: (A) exon 4 mutation (R192Q) in family It-II is recognized by SfcI digestion; control DNA consisted of DNA mixture of three unrelated individuals, (C) mutation V714A in family UK-B leads to additional BbvI site, and (D), mutation I1811L in families NL-A and US-C is detected by gain of MnlI restriction site. SSCP analysis: (B) aberrant SSCP conformers represent cosegregation of T666M mutation within family US-P. Arrows indicate positions of the aberrant bands in FHM affected individuals. Cell 1996 87, 543-552DOI: (10.1016/S0092-8674(00)81373-2)

Figure 4 Mutation Detection in the CACNL1A4 Gene in FHM Families Detection of four CACNL1A4 missense mutations in five different FHM families by restriction site (A, C, and D) or SSCP (B) analysis of PCR products. All missense mutations cosegregate with the disease within the families. Restriction site analysis: (A) exon 4 mutation (R192Q) in family It-II is recognized by SfcI digestion; control DNA consisted of DNA mixture of three unrelated individuals, (C) mutation V714A in family UK-B leads to additional BbvI site, and (D), mutation I1811L in families NL-A and US-C is detected by gain of MnlI restriction site. SSCP analysis: (B) aberrant SSCP conformers represent cosegregation of T666M mutation within family US-P. Arrows indicate positions of the aberrant bands in FHM affected individuals. Cell 1996 87, 543-552DOI: (10.1016/S0092-8674(00)81373-2)

Figure 4 Mutation Detection in the CACNL1A4 Gene in FHM Families Detection of four CACNL1A4 missense mutations in five different FHM families by restriction site (A, C, and D) or SSCP (B) analysis of PCR products. All missense mutations cosegregate with the disease within the families. Restriction site analysis: (A) exon 4 mutation (R192Q) in family It-II is recognized by SfcI digestion; control DNA consisted of DNA mixture of three unrelated individuals, (C) mutation V714A in family UK-B leads to additional BbvI site, and (D), mutation I1811L in families NL-A and US-C is detected by gain of MnlI restriction site. SSCP analysis: (B) aberrant SSCP conformers represent cosegregation of T666M mutation within family US-P. Arrows indicate positions of the aberrant bands in FHM affected individuals. Cell 1996 87, 543-552DOI: (10.1016/S0092-8674(00)81373-2)

Figure 4 Mutation Detection in the CACNL1A4 Gene in FHM Families Detection of four CACNL1A4 missense mutations in five different FHM families by restriction site (A, C, and D) or SSCP (B) analysis of PCR products. All missense mutations cosegregate with the disease within the families. Restriction site analysis: (A) exon 4 mutation (R192Q) in family It-II is recognized by SfcI digestion; control DNA consisted of DNA mixture of three unrelated individuals, (C) mutation V714A in family UK-B leads to additional BbvI site, and (D), mutation I1811L in families NL-A and US-C is detected by gain of MnlI restriction site. SSCP analysis: (B) aberrant SSCP conformers represent cosegregation of T666M mutation within family US-P. Arrows indicate positions of the aberrant bands in FHM affected individuals. Cell 1996 87, 543-552DOI: (10.1016/S0092-8674(00)81373-2)

Figure 5 Mutation Detection in the CACNL1A4 Gene in EA-2 Families Demonstration of EA-2 mutations by restriction site analysis of CACNL1A4 PCR products: (A) one basepair deletion (ΔC4073) in CAN-191 leads to loss of NlaIV restriction site in exon 22; (B) splice site mutation in intron 24 is shown by loss of BsaAI site in family CAN-26. Cell 1996 87, 543-552DOI: (10.1016/S0092-8674(00)81373-2)

Figure 6 Mutation Screening by Denaturing High Performance Liquid Chromatography (DHPLC) Chromatograms of DHPLC analysis of heterozygote PCR product at increasing mobile phase temperatures (57°C–61°C). Successful resolution of heteroduplex signal of exon 32 of family member of NL-A was accomplished at 61°C. Cell 1996 87, 543-552DOI: (10.1016/S0092-8674(00)81373-2)