Molecular genetic and genetic correlations in sodium channelopathies : lack of founder effect and evidence for a second gene

• Published in: American journal of human genetics 1993-06, Vol.52 (6), p.1074-1084
• Main Authors: WANG, J, ZHOU, J, SILLEN, A, MARKS, H. G, HARTLAGE, P, GALLOWAY, G, RICKER, K, LEHMANN-HORN, F, HAYAKAWA, H, HOFFMAN, E. P, TODOROVIC, S. M, FEERO, W. G, BARANY, F, CONWIT, R, HAUSMANOWA-PETRUSEWICZ, I, FIDZIANSKA, A, ARAHATA, K, WESSEL, H. B
• Format: Article
• Language: English
• Subjects: Adult; ALKALI METALS; BASIC BIOLOGICAL SCIENCES; Biological and medical sciences; BIOLOGICAL VARIABILITY; Child, Preschool; Cohort Studies; DISEASES; Diseases of striated muscles. Neuromuscular diseases; ELEMENTS; Female; GENE MUTATIONS; GENES; GENETIC VARIABILITY; Haplotypes; Humans; Infant; Male; Medical sciences; MEMBRANE PROTEINS; METABOLIC DISEASES; METALS; Middle Aged; MUSCLES; Muscles - metabolism; MUTATIONS; Myotonia Congenita - genetics; Neurology; Oligodeoxyribonucleotides; ORGANIC COMPOUNDS; Original; Paralyses, Familial Periodic - genetics; Pedigree; Polymorphism, Genetic; PROTEINS 550400 > Genetics; Repetitive Sequences, Nucleic Acid; RFLPS; SODIUM; Sodium Channels - genetics
• ISSN: 0002-9297; 1537-6605

We present a correlation of molecular genetic data (mutations) and genetic data (dinucleotide-repeat polymorphisms) for a cohort of seven hyperkalemic periodic paralysis (HyperPP) and two paramyotonia congenita (PC) families from diverse ethnic backgrounds. We found that each of three previously identified point mutations of the adult skeletal muscle sodium-channel gene occurred on two different dinucleotide-repeat haplotypes. These results indicate that dinucleotide-repeat haplotypes are not predictive of allelic heterogeneity in sodium channelopathies, contrary to previous suggestions. In addition, we identified a HyperPP pedigree in which the dominant disorder was not linked to the sodium-channel gene. Thus, a second locus can give rise to a similar clinical phenotype. Some individuals in this pedigree exhibited a base change causing the nonconservative substitution of an evolutionarily conserved amino acid. Because this change was not present in 240 normal chromosomes and was near another HyperPP mutation, is fulfilled the most commonly used criteria for being a mutation rather than a polymorphism. However, linkage studies using single-strand conformation polymorphism-derived and sequence-derived haplotypes excluded this base change as a causative mutation: these data serve as a cautionary example of potential pitfalls in the delineation of change-of-function point mutations.