How about a News Release on the Risk Factors For Autism, Headed By Older Paternal Age, Older Maternal Grandfather's Age, Family History of Autoimmune

Disorders, Family history of Asperger's, Family history of autism, Family history of Schizophrenia, family history of OCD disorders. By the age of 35 it is advanced paternal age. Some sperm banks cut off donations of sperm at the 35th birthday, some in Africa and Israel cut off sperm donors at the 30th birthday. There definetly is a male biological clock and advanced paternal age 32++++++ equals genetic disorders. Cancers, heart defects, Alzheimer's, Duchennes, hemophilia, diabetes, MS, Crohn's, etc. etc. increase with increasing paternal age and increasing maternal grandfather's age at the mother's birth.


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Researchers Reveal Structure of Protein Altered in Autism


Source: University of California, San Diego Health Sciences Released: Wed 06-Jun-2007, 19:15 ET
Embargo expired: Tue 12-Jun-2007, 12:00 ET Printer-friendly Version



As a result of mapping the structure of the protein complex implicated in autism spectrum disorders, a research team led by scientists at theUCSD Skaggs School of Pharmacy and Pharmaceutical Sciences has discovered how particular genetic mutations affect this complex and contribute to the developmental abnormalities found in children with autism.



Newswise — As a result of mapping the structure of the protein complex implicated in autism spectrum disorders, a research team led by scientists at the University of California, San Diego (UCSD) Skaggs School of Pharmacy and Pharmaceutical Sciences has discovered how particular genetic mutations affect this complex and contribute to the developmental abnormalities found in children with autism. Their work, published as the cover article in the June issue of the journal Structure, should help scientists pinpoint the consequences of other genetic abnormalities associated with the disorder.

“By understanding the three-dimensional structure of the normal protein, researchers can now make predictions about how mutations in the gene affect the structure of the gene product,” said first author Davide Comoletti, Ph.D., UCSD research associate at the Skaggs School of Pharmacy.

Autism spectrum disorders are developmental disabilities that cause impairments in social interaction and communication. Both children and adults with autism typically show difficulties in verbal and non-verbal communication, interpersonal relationships, and leisure or play activities.

Comoletti and colleagues studied the neuroligin family of proteins that are encoded by genes known to be mutated in certain patients with autism. The neuroligins, and their partner proteins, the neurexins, are involved in the junctions, or synapses, through which cells of the nervous system signal to one another and to non-neuronal tissues such as muscle. These structural studies on neuroligins and neurexins represent a major step toward defining the synaptic organization at the molecular level.

“Normally, individual neuroligins are encoded to interact with specific neurexin partners. The two partners are members of distinct families of proteins involved in synaptic adhesions, imparting ‘stickiness’ that enables them to associate so that synapses form and have the capacity for neurotransmission,” said Palmer Taylor, Ph.D., Dean of the Skaggs School, Sandra & Monroe Trout Professor of Pharmacology, and co-principal investigator of the study, along with Jill Trewhella, Ph.D., of the University of Sydney, Australia and University of Utah.

Incorrect partnering that results when a mutant neuroligin fails to properly align at synapses helps explain why the autism spectrum disorders are manifested in subtle behavioral abnormalities that are seen at an early age.

“Abnormal synaptic development in nerve connections is likely to lead to cognitive deficits seen in patients with autism,” said Taylor. He added that synapse formation and maintenance occurs early in development when the infant brain is still plastic and formative. Therefore, by understanding the structural mutations that affect neurotransmission during development, new leads into drug therapies may emerge.

“We really don’t know what causes autism, but this research represents a solid starting point,” said Sarah Dunsmore, Ph.D., program director with the National Institute of General Medical Sciences, part of the National Institutes of Health, which partly supported the study. “The work suggests that genetic mutations that alter the shape or folding of adhesion proteins in the nervous system influence their interactions. This is another example of how research on basic biological questions, such as the three-dimensional structures of proteins in the brain, can yield valuable medical insights.”

Taylor and colleagues have been studying the structure and function of acetylcholinesterase – a structurally related protein that mediates neurotransmission between nerves and between nerve and muscle – for the past 30 years. They began studying the neuroligins because of the similarity in structure and amino acid sequence with acetylcholinesterase.

The study was a multi-national collaboration, employing synchrotrons at two national laboratories to collect the X-ray and neutron scattering data necessary for resolving the structure. Additional contributors to this study include Alexander Grishaev, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD; Andrew E. Whitten, Bragg Institute, Australian Nuclear Science and Technology Organization; and Igor Tsigelny, UCSD Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences.

This work was supported in part by grants from the National Institutes of Health, the U.S. Department of Energy, and the Cure Autism Now Foundation.

BACK TO THE SUBJECT OF COPY NUMBER VARIATIONS IN SPORADIC AUTISM IN 10% OF THE OFFSPRING IN SEBAT AND WIGLER'S STUDY? IS IT DAD'S SPERM?

Genomics & Proteomics
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We tested the hypothesis that de novo copy number variation (CNV) is associated with autism
spectrum disorders (ASDs). We performed comparative genomic hybridization (CGH) on the
genomic DNA of patients and unaffected subjects to detect copy number variants not present in
their respective parents. Candidate genomic regions were validated by higher-resolution CGH,
paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping.
Confirmed de novo CNVs were significantly associated with autism (P = 0.0005). Such CNVs were
identified in 12 out of 118 (10%) of patients with sporadic autism, in 2 out of 77 (3%) of patients
with an affected first-degree relative, and in 2 out of 196 (1%) of controls. Most de novo CNVs
were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous
and included mutations of single genes. These findings establish de novo germline mutation as a
more significant risk factor for ASD than previously recognized.

'THERE IS NO EVIDENCE THAT THE RISK OF A DE NOVO CNV IS RELATED TO THE AGE OF EITHER PARENT"

~ARTHUR L. BEAUDET

THIS IS INTRIGUING, IS THERE EVIDENCE THAT DE NOVO CNVs ARE NOT RELATED TO AGE?
Scientists are not sure why the copy variations emerge, but it probably has something to do with the shuffling of genetic material that occurs in the production of eggs and sperm; the process is prone to errors.

"De novo point mutations in such genes could explain the advanced paternal age association that has been reported for autism13. There is no evidence, however, that the risk of a de novo CNV is related to the age of either parent."




There are several CNVs are associated with 17 conditions of the nervous system including Parkinsons and Alzheimer's disease. Sebat and Wigler et al. have found them in sporadic autism. Also there are CNVs involved in the genes that are involved with the immune system and in human evolution.

CNVs PROBABLY HAVE TO DO WITH IN THE SHUFFLING OF GENETIC MATERIAL THAT OCCURS IN THE PRODUCTION OF EGGS AND SPERM

The new understanding will change the way in which scientists search for genes involved in disease.

"Many examples of diseases resulting from changes in copy number are emerging," commented Charles Lee, one of the project's leaders from Brigham and Women's Hospital and Harvard Medical School in Boston, US.


"A recent review lists 17 conditions of the nervous system alone - including Parkinson's disease and Alzheimer's disease - that can result from such copy number changes."
Scientists are not sure why the copy variations emerge, but it probably has something to do with the shuffling of genetic material that occurs in the production of eggs and sperm; the process is prone to errors. As well as aiding the investigation of disease and the development of new drugs, the research will also inform the study of human evolution, which probes genetic variation in modern populations for what it can say about their relationship to ancestral peoples.

SPERMATOGONIA, SPERMATOGONIUM

Spermatogonium
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Spermatogonium

Germinal epithelium of the testicle. 1 basal lamina, 2 spermatogonia, 3 spermatocyte 1st order, 4 spermatocyte 2nd order, 5 spermatid, 6 mature spermatid, 7 Sertoli cell, 8 tight junction (blood testis barrier)


A spermatogonium (plural: spermatogonia) is an intermediary male gametogonium (a kind of germ cell) in the production of spermatozoa.

There are two subtypes:

Type A(d) cells have dark nuclei and they divide to produce copies of themselves, thereby ensuring a constant supply of spermatogonia to fuel spermatogenesis.

Type A(p) cells have pale nuclei and they divide by mitosis to produce Type B cells and these Type B cells divide again to give rise to primary spermatocytes.

Each primary spermatocyte duplicates its DNA and subsequently undergoes meiosis I to produce two haploid secondary spermatocytes. Each of the two secondary spermatocytes further undergo meiosis II to produce two spermatids (haploid). (1 primary spermatocytes => 4 spermatids)

The spermatids then undergo spermiogenesis to produce spermatozoa.


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