Abstract
De novo dominant mutations in the GFAP gene have recently been associated with nearly all cases of Alexander disease, a rare but devastating neurological disorder. These heterozygous mutations must occur very early in development and be present in nearly all cells in order to be detected by the sequencing methods used. To investigate whether the mutations may have arisen in the parental germ lines, we determined the parental chromosome bearing the mutations for 28 independent Alexander disease cases. These cases included 17 different missense mutations and one insertion mutation. To enable assignment of the chromosomal origin of the mutations, six new single nucleotide polymorphisms in the GFAP gene were identified, bringing the known total to 26. In 24 of the 28 cases analyzed, the paternal chromosome carried the GFAP mutation (P<0.001), suggesting that they predominantly arose in the parental germ line, with most occurring during spermatogenesis. No effect of paternal age was observed. There has been considerable debate about the magnitude of the male to female germ line mutation rate; our ratio of 6:1 is consistent with indirect estimates based on the rate of evolution of the sex chromosome relative to the autosomic chromosomes.
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Acknowledgements
We are indebted to the patients and their families for participating in this study. We thank Robecca Anderson for technical assistance in all phases of this research. Human tissues and case information were graciously provided by Drs. Enrico Bertini, Barbara Burton, Amanda Collins, Marc D’Hooghe, Luis González Gutiérrez-Solana, Alyssa Reddy, Cristin M. Rolf and Joseph Siebert; and also were obtained from the NICHD Brain and Tissue Bank for Developmental Disorders under NICHD contracts N01-HD-43368 and NO1-HD-8–3284; from the National Neurological Research Specimen Bank, VAMC, Los Angeles, CA 90073, sponsored by NINDS/NIMH, the National Multiple Sclerosis Society, the Hereditary Disease Foundation, and the Veterans Health Services and Research Administration, Department of Veterans Affairs; and from the Laboratorio di Diagnosi Pre e Postnatale delle Malattie Metaboliche (Instituto G. Gaslini; supported by Telethon project C.20). We also thank the AECOM Human Genetics Program for preparation of lymphoblasts and DNA samples, the UAB MMRC Molecular Biology Core for recombinant DNA support, and the UAB Genomics Core Facility of the Howell and Elizabeth Heflin Center for Human Genetics for DNA sequencing. MB, JEG and AM were supported by NINDS grant P01NS42803; MB was also supported by MRRC grant P30HD38985 and the Lei Foundation, and AM by MRRC grant P30HD03352; ABJ was supported in part by the United Leukodystrophy Foundation; DR was supported in part by the European Leukodystrophy Association (ELA) and the Fédération des Maladies Orphelines (FMO).
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Li, R., Johnson, A.B., Salomons, G.S. et al. Propensity for paternal inheritance of de novo mutations in Alexander disease. Hum Genet 119, 137–144 (2006). https://doi.org/10.1007/s00439-005-0116-7
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DOI: https://doi.org/10.1007/s00439-005-0116-7