A NRXN1 PATERNAL GERM-LINE MUTATION (IN SPERM ONLY) CAUSES AUTISM IN TWO DAUGHTERS

The finding is interesting. The question you have raised is a difficult one. Currently there is no sure way to know exactly when the parental germline mosaicism was first established. The size of the mosaicism may tell a partial story. For example, the presence of large, extensive germline mosaicism probably implies that a germ-line mutation event had occurred early (perhaps when the father was in the embryonic stage). I am trying to develop a new method that can narrow down the timing of germ-line mutation events. But it may take me a while to get the research funding needed to complete the project. Most researchers do not believe that germ-line mosaicism is a major source of contribution to human birth defects - a view I feel impedes our understanding about the orgin of human birth defects.

"This is a direct attempt on the part of the authors to insure that confidentiality is maintained, which of course is a critical issue in such sensitive genetics research."

"The reason is that the deletion is identical in the two siblings. For two identical deletions to occur in different sperm by chance is so unlikely as to be almost inconceivable. The deletion had to come from a progenitor sperm cell, and is unlikely to be related to the paternal age effect reported in autism."


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Germ line mosaicism Presence of 2 or more cell lines that differ in genetic makeup among gametes (germ cells); implies risk of transmission of mutations present in the gonads to offspring. Cf. mosaicism
Related Terms: Gamete Mature male or female reproductive cell (sperm or ovum) with a haploid set of chromosomes (23 for humans).
Mutation The term which De Vries introduced into biological literature for an abrupt change of genotype which is inherited. Any permanent and heritable change in DNA sequence. Types of mutations include point mutations, deletions, insertions, and changes in number and structure of chromosomes. (Cf. polymorphism)
Mosaicism Condition in which an individual harbors 2 or more genetically distinct cell lines; results from a genetic change after formation of a zygote, ie postzygotic event. Cf. germ line mosaicism.








Abstract
Primary Author's Institution/Affiliation
University of Iowa Carver College of Medicine

A NRXN1 PATERNAL GERM-LINE MUTATION CAUSING AUTISM IN TWO FEMALE SIBLINGS

THERE IS NO PROOF GIVEN THAT THIS IS A TRUE GESTATIONAL MOSAICISM AND NOT A STRUCTURAL CHROMOSOME ABERRATION DUE TO ADVANCED PATERNAL AGE

IT WOULD BE IMPORTANT TO HAVE MORE INFORMATION ABOUT THE FATHER OF THE TWO DAUGHTERS:
HIS AGE IS OCCUPATION ETC.ETC. NO ONE WILL TELL ME THE AGE OF THIS FATHER, EITHER THEY DON'T ANSWER MY E-MAILS REQUESTING MORE INFORMATION OR THEY TELL ME IT IS A MATTER OF SUBJECT CONFIDENTIALITY. THIS IS NOT SCIENCE.



T. H. Wassink, K. J. Meyer, E. M. Stone, V. C. Sheffield, . Autism Genome Project
Enter abstract here-DON'T include authors or title
BACKGROUND: The AGP performed a 10k SNP screen on 1496 multiplex autism families. Examination of the SNP data for genomic copy number variation revealed a deletion in the Neurexin 1 gene (NRXN1) in two female siblings with autism.

OBJECTIVES: 1) Characterize the NRXN1 deletion; 2) Screen a large sample of individuals with autism for NRXN1 mutations; 3) Test the AGP data for evidence of linkage disequilibrium (LD) at NRXN1.

METHODS: 1) qPCR and genotyping of polymorphic markers was performed in the deletion family. 2) 400 individuals with autism were screened for mutations in NRXN1-b using SSCP analysis. Gel shifts were sequenced, and novel variants were sequenced in the entire families in which they were found. 3) Four NRXN1 SNPs were tested for LD in the AGP families with the FBAT empirical statistic.


RESULTS: 1) qPCR confirmed the NRXN1 deletions in the siblings. Polymorphic markers showed no transmission of paternal alleles, indicating a germ-line mutation as the causative event. The deletion interval was narrowed to ~450 kb that includes the midsection of NRXN1-a and the promoter region and exons 1 and 2 of NRXN1-b. 2) No novel missense or nonsense variants were found. A number of novel synonymous and non-coding variants were identified that are of unclear significance. 3) Biased transmission was noted under a dominant model of inheritance for rs1363036 (p=0.0091) and rs930752 (p=0.025); rs930752 also showed biased transmission under an additive model (p=0.014). These intronic SNPs are in modest LD (r2=0.048).

CONCLUSIONS: Paternal germ-line mosaicism of NRXN1 appears to cause autism in the deletion family, though similar causative mutations are likely to be rare. More common NRXN1 variants, however, may contribute to autism susceptibility. This finding is of interest given recent data implicating germ-line mosaicism and mutations of cortical excitatory synapse genes (e.g., NLGN and SHANK) in the etiology of autism.

SPONSOR: Autism Speaks, NIH



THE PRESS RELEASE


Medical Research News
Published: Sunday, 6-May-2007
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University of Iowa researchers have learned more about a genetic mutation that contributes to autism.
The mutation occurred in sperm cells of a father, who does not have autism, but passed the condition on to two of his children.

The investigators now know more about how the mutation causes problems with a specific gene and are testing for additional mutations of the same gene in other people with autism. Thomas Wassink, M.D., associate professor of psychiatry in the UI Carver College of Medicine, is presenting the findings May 3 at the annual International Meeting for Autism Research in Seattle.

Earlier this year, UI researchers and collaborators were part of an international team that identified, among other findings, deletions in a gene called neurexin 1, which caused the two cases of autism in one family. The UI researchers and collaborators were Wassink; Val Sheffield, M.D., Ph.D., UI professor of pediatrics and a Howard Hughes Medical Investigator; Kacie Meyer, a graduate student in Wassink's laboratory; and former UI investigator Joseph Piven, M.D., now professor of psychiatry at the University of North Carolina (UNC) and director of the UNC Neurodevelopmental Disorders Research Center,

"Genes with the most compelling evidence of causing autism appear to be components of a specific kind of neuronal connection, or synapse, called the glutamate synapse. The gene neurexin 1 was the fourth of these genes to be identified, and it is a scientifically interesting mutation because it wasn't found in either of the parents, who do not have autism," Wassink said.

Instead, the mutation is a germline mosaic -- meaning the deletion occurred only in the father's sperm cells when he himself was in gestation. As result, the father did not have autism, but his two children, both daughters, inherited from him a chromosome that was missing a small piece of DNA that contained neurexin 1. The daughters now have autism.

Because of this missing DNA, certain proteins cannot form that normally contribute to glutamate synapses and, by extension, normal development.

"Now, using this information, we can look in a very detailed way at this gene in other families and begin to understand what happens when this protein that is normally active in the brain is missing," Wassink said.

Knowing more about how the deletions function could eventually lead to the development of diagnostic and therapeutic tools.

http://www.uiowa.edu


THIS IS JUST A STATEMENT---MAYBE TRUE---MAYBE NOT TRUE----THE MUTATION MAY BE A PATERNAL AGE OR TOXIN DERIVED ABERRATION OF CHROMOSOME 11p

Instead, the mutation is a germline mosaic -- meaning the deletion occurred only in the father's sperm cells when he himself was in gestation. As result, the father did not have autism, but his two children, both daughters, inherited from him a chromosome that was missing a small piece of DNA that contained neurexin 1. The daughters now have autism.