Recurrence of the T666M Calcium Channel CACNA1A Gene Mutation in Familial Hemiplegic Migraine with Progressive Cerebellar Ataxia A. Ducros, C. Denier,

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Recurrence of the T666M Calcium Channel CACNA1A Gene Mutation in Familial Hemiplegic Migraine with Progressive Cerebellar Ataxia A. Ducros, C. Denier, A. Joutel, K. Vahedi, A. Michel, F. Darcel, M. Madigand, D. Guerouaou, F. Tison, J. Julien, E. Hirsch, F. Chedru, C. Bisgård, G. Lucotte, P. Després, C. Billard, M.A. Barthez, G. Ponsot, M.G. Bousser, E. Tournier-Lasserve The American Journal of Human Genetics Volume 64, Issue 1, Pages 89-98 (January 1999) DOI: 10.1086/302192 Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 1 T666M mutation in nine families and one nonfamilial case of HM/PCA. a, Pedigrees of the 16 families and the 3 nonfamilial case patients. Individuals are represented as males (squares), females (circles), unaffected (unblackened symbol), affected (blackened symbol), and having an unknown status (hatched symbol). A question mark (?) indicates subjects for whom no history was available. Probands are indicated by an asterisk (*). All living subjects represented on this figure were sampled, except in families F8, F9, F15, and F16, in which only the proband was sampled, and the nonfamilial case S1, from whose parents blood had not been drawn. b, T666M abnormal conformers. SSCP was performed with DNA from the 16 family probands and the 3 nonfamilial case patients. SSCP and DNA sequencing revealed the same C→T substitution at codon 666, substituting a threonine for a methionine (T666M) in nine families (F1–F9) and in sporadic case S1. The banding pattern of a normal control (N) is also shown. c, Cosegregation of the T666M mutation with HM/PCA was demonstrated by SSCP in each multiplex family, as shown here for part of family F5. The numbering in this part of family F5 is given according to the gel lanes. All affected members are heterozygous for the wild type and the mutant sequence, and all unaffected subjects (10 and 11) and unrelated spouses (3, 7, and 14) are homozygous for the normal sequence. The American Journal of Human Genetics 1999 64, 89-98DOI: (10.1086/302192) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 2 Mutation D715E in exon 17 of the CACNA1A gene in family F10. a, SSCP and DNA sequence analysis of individual F10-4 revealed a C→G substitution at codon 715, resulting in a substitution of an aspartic acid for a glutamic acid. b, The cosegregation of this mutation with HM/PCA was demonstrated in family F10 by the SSCP analysis of 16 of the 20 family members. The numbering in this part of family F10 is given according to the gel lanes. All affected members are heterozygous (wt/m). All unaffected spouses are homozygous for the wild-type sequence. Individual 9, a 24-year-old man free of any migraine attack and with normal neurologic findings on examination, is heterozygous (wt/m). In the 90 HM/PCA patients in this study, the mean age of onset was 11.4 years old, but in 7% of those patients, attacks started after 24 years of age. Individual 9 may represent an instance of nonpenetrance or a case of delayed onset. The American Journal of Human Genetics 1999 64, 89-98DOI: (10.1086/302192) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 3 α1A subunit missense mutations causing HM/PCA and pure HM. A schematic structure of the α1A calcium channel subunit is drawn, and positions of all HM causing mutations identified thus far are indicated. The American Journal of Human Genetics 1999 64, 89-98DOI: (10.1086/302192) Copyright © 1999 The American Society of Human Genetics Terms and Conditions