Thursday, July 5, 2007

The paternal component of this parental age effect was the major factor in the occurrence of such mutations

Genetika. 1984 Oct;20(10):1726-32.Links
[Analysis of the relation of the frequency of new gene mutations for Mendelian diseases to parental age][Article in Russian]

Bazhenova MD, Kozlova SI, Al'tshuler BA, Tatishvili GG.
The effect of parental age on mutation rates of achondroplasia, neurophibromatosis, hereditary gastrointestinal adenomatosis and Duchenne muscular dystrophy loci was studied. A significant parental age effect on the occurrence of new mutations for achondroplasia and neurophybromatosis was shown. The paternal component of this parental age effect was the major factor in the occurrence of such mutations. The risk of the occurrence of new cases of achondroplasia and neurophybromatosis, as compared with their overall frequency, due to new mutations, are increased by a factor of 2 and 3, respectively, up to the paternal age of 50. The possibility of application of the data obtained in genetic counselling is discussed.

PMID: 6149974 [PubMed - indexed for MEDLINE]

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Duchenne New Mutants Could Be Prevented With Younger Paternal Age At Conception

: J Med Genet. 1978 Oct;15(5):339-45.Links
Estimation of proportion of new mutants among cases of Duchenne muscular dystrophy.Davie AM, Emery AE.
Using a number of different methods, it is confirmed that approximately one third of all cases of X-linked Duchenne muscular dystrophy are new mutants, the remainder being sons of carriers.

1: Am J Med Genet. 1980;7(1):27-34.Links
Frequency of new mutants among boys with Duchenne muscular dystrophy.Bucher K, Ionasescu V, Hanson J.
Haldane's rule states that one-third of the cases of an X-linked recessive lethal should represent new mutations. This rule is derived under the assumptions that there is equilibrium between mutation and selection, that mutation rates in ova and sperm are equal, and that heterozygous and homozygous normal women have the same fitness. To test this rule for Duchenne muscular dystrophy (DMD), we have examined the mothers of 55 boys with DMD (16 familial and 39 isolated cases) and classified them as carriers or noncarriers on the basis of measures of ribosomal protein synthesis (RPS). Of the 55 mothers, only nine (16.4%) are classified as noncarriers, a figure significantly different from the expected one-third. When the analysis is limited to the 39 mothers of isolated cases, 23.1% (9/39) are classified as noncarriers, still significantly different than expected under Haldane's rule. Violation of any of the assumptions under which Haldane's rule is derived could lead to deviations from the expected one-third new mutants. We find the most likely explantation to be a higher male than female mutation rate. This is supported also by the finding that maternal grandfathers in whom a mutation occurred had higher mean age at birth of the carrier daughter (33.7 +/- 1.6) than did the general population or intrapedigree controls (29.5 +/- 1.3).PMID: 7211951 [PubMed - indexed for MEDLINE]


Monday, July 2, 2007

CHD7 Gene and Scoliosis Maternal Age??? Or is Paternal Age Involved???

Physicians have recognized scoliosis, the abnormal curvature of the spine, since the time of Hippocrates, but its causes have remained a mystery -- until now. For the first time, researchers have discovered a gene that underlies the condition, which affects about 3 percent of all children.

The new finding lays the groundwork for determining how a defect in the gene -- known as CHD7 -- leads to the C- and S-shaped curves that characterize scoliosis. The gene's link to scoliosis was identified by scientists at Washington University School of Medicine in St. Louis, working in collaboration with investigators at the University of Texas Southwestern Medical Center and Texas Scottish Rite Hospital for Children, both in Dallas, Rutgers State University of New Jersey and the University of Iowa. The group published its results in May in the American Journal of Human Genetics.

"Hopefully, we can now begin to understand the steps by which the gene affects spinal development," says Anne Bowcock, Ph.D., professor of genetics, of medicine and of pediatrics. "If we understand the genetic basis of the condition, we can theoretically predict who is going to develop scoliosis and develop treatments to intervene before the deformity sets in. It may take many years to accomplish these goals, but I think it will eventually happen."

The researchers have traced a defect in CHD7 to idiopathic scoliosis, the form of the condition for which there is no apparent cause. It is the most common type of scoliosis, occurs in otherwise healthy children and is typically detected during the growth spurt that accompanies adolescence.

Although scientists have known for years that scoliosis runs in families, its pattern of inheritance has remained unclear. That's because the condition is likely caused by several different genes that work in concert with one another -- and the environment -- to cause scoliosis. Bowcock predicts that scientists will soon find other genes involved in the disease.

The CHD7 gene is thought to play a critical role in many basic functions in the cell. The researchers zeroed in on the gene after finding that it is missing or profoundly disrupted in a rare syndrome called CHARGE. Babies born with the syndrome often die in infancy. Those that survive have heart defects, mental retardation, genital and urinary problems, ear abnormalities and deafness, among other problems. They also develop late-onset scoliosis.

"This led us to consider that milder variations of CHD7 may be involved in other types of scoliosis," Bowcock said.

The researchers, led by Carol Wise, Ph.D., at Scottish Rite Hospital, collected data on 52 families with a history of scoliosis in at least two members -- the one who sought treatment and another from earlier generation. The patients had an average spinal curvature of 40 degrees and did not have any illnesses, such as Marfan syndrome or cerebral palsy, which can also involve scoliosis. The researchers performed genome-wide scans that spelled out the 6 billion letters of genetic code in the affected family members and analyzed the data.

They found that patients with scoliosis very often had a defect in the gene's non-coding region, meaning that the error did not disrupt production of the CHD7 protein. The researchers speculate that this particular mutation alters the binding of a molecule that controls whether the gene is turned on. In this case, they think the gene is turned off more often than it should be, which reduces the amount of CHD7 protein produced.

"The change in the amount of the protein produced is subtle, which correlates with the onset of scoliosis, which typically happens very gradually," explains Michael Lovett, Ph.D., professor of genetics and pediatrics. "This particular defect was so highly associated with scoliosis that it is either the real McCoy or is very closely linked to the defect that causes the condition."

The researchers will continue to look for genetic variations involved in scoliosis by studying additional families with the condition.

Severe scoliosis is typically treated by surgery or by wearing an orthopedic brace, which straightens the curvature over time. Most minor spinal curves can be monitored by a doctor and do not progress to the point where treatment is necessary.


1: J Bone Joint Surg Am. 1990 Jul;72(6):910-3. Related Articles, Links

Influence of parental age on degree of curvature in idiopathic scoliosis.

Henderson MH, Rieger MA, Miller F, Kaelin A.

Department of Medical Education, Alfred I. duPont Institute, Wilmington, Delaware 19899.

One hundred and seventy-seven patients who had adolescent idiopathic scoliosis were followed from the time of the initial evaluation to skeletal maturity or arthrodesis. At that time, we analyzed the degree of curvature to determine if it was related to parental age at the time of the patient's birth. Patients who were born to mothers who were twenty-seven years old or more had a mean curve of 35.2 degrees, which was significantly greater (p = 0.02) than that of patients whose mothers were younger than twenty-seven years, who had a mean curve of 30.4 degrees. More patients whose mothers were twenty-seven years old or older ultimately needed arthrodesis than did those whose mothers were younger than twenty-seven years (26 compared with 12 per cent). Therefore, a maternal age of twenty-seven years old or more is a risk factor for greater progression of the curve and indicates a potential need for arthrodesis. No difference in the degree of curvature was seen when the patients were grouped according to paternal age.

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"Common KIBRA alleles are associated with human memory performance

Genetics of Human Memory Performance

December 2006

Researchers at the Translational Genomics Research Institute (TGen) in Phoenix and the University of Zurich have discovered a genetic variation in the human KIBRA gene associated with short-term memory performance, a finding that may shed light on devastating memory-based diseases such as Alzheimer's and Parkinson's.

"This is a generally applicable association finding," said Dietrich Stephan, head of the Neurobehavioral Research Unit at TGen. "In fact, probably about 50 percent of people worldwide have the at-risk haplotype and about 50 percent have the good haplotype."

The team, led by Stephan and Andreas Papassotiropoulos, made the discovery using the Affymetrix Human Mapping 500K Array Set; the study is the first published research using genotype data from 500,000 SNPs for whole-genome association analyses.

"Whole-genome association works at this density in outbred populations," said Stephan. "The ramifications for understanding disease process and for early diagnostics are huge."

Stephan's team discovered that genetic changes in the gene encoding the KIBRA protein correlated with the ability to perform memory-based tasks in a cohort of 341 students at the University of Zurich. They confirmed this association in additional Swiss and U.S. cohorts.

Gene expression studies showed that the KIBRA transcript is present at high levels in the human brain, especially in the hippocampus, a part of the brain critical in memory function. The team also performed functional magnetic resonance imaging, which showed that activation in the hippocampus during memory retrieval differs depending on the KIBRA allele.

The study, "Common KIBRA alleles are associated with human memory performance," appears in the October 20, 2006, issue of Science.


Sunday, July 1, 2007

Rates of birth defects such as achondroplasia (short stature) and autism is higher among children with older fathers. Single and multi gene disorders

"It is curious that although sperm have been around since the beginning of time, we know so little about what is in them, and what makes them tick, er, swim. So scientists spend a lot of their waking hours trying to compare the structure and content of the proteins of sperm in various species, in order to understand their evolution and origin. For instance, the mutated DNA in the genes of the sperm of older fathers is believed to cause many genetic diseases. It is almost as if a man’s biological clock accelerates mutation in sperm cells in his early ’30s."


Birth Defects Higher Among Children with Older Fathers

Older men have an increased risk of having a child with abnormalities, new research suggests.

The common belief is that there is no age limit for men when it comes to fathering a child. Unlike women who undergo menopause, men do not have a fixed “andropause”. However, this view is being challenged as new evidence shows that the rates of birth defects such as achondroplasia (short stature) and autism is higher among children with older fathers.

A recent study carried out at a large Israeli army database found that children of men over 40 were 5.75 times more likely to have an autism disorder than those who had fathers under 30. Another Israeli study suggested that the risk of schizophrenia in children is almost double if the father is in his late 40s.

Prof Sheena Lewis, a consultant in reproductive medicine at Queen's University Belfast, said that as men get older their sperm DNA becomes more fragmented. By the time a man is 50, the cells that create a man’s sperm have replicated up to 800 times, creating many possibilities for error.

According to Prof Lewis:

The impact of the father smoking is even worse than the mother smoking (you can't repair damage caused in sperm DNA)
Viagra can affect fertility by causing the sperm to travel too fast
Cannabis us slows sperm function, resulting in a reduction in fertility
She also warns about the damaging impact of modern lifestyle and environmental factors.


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