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Sunday, 18 November 2007

Marfan Syndrome

[Compiled by GenePool] [May 2006] [ Author : June-Anne Gold- Specialist Registrar Clinical Genetics]
The Least You Need to Know
1.It can present at any age – (rarely as a severe neonatal form.)
2.Any one of the systems may make you think of the diagnosis. o Eyes- myopia/lens dislocation/detached retinao Heart- dilatation, dissection or rupture of the aortao Lungs- spontaneous pneumothorax.o Skeleton- tall and thin, long limbs and fingers and toes, spinal curvature.
3.Sudden early death due to cardiac cause in family history.
4.Definitive diagnosis may be made by a cardiologist, but referral to a clinical genetics centre is advisable in order to counsel the whole family.

Mothers concern that theirs children are too tall.

Growing up, Roan Apolonio was always seated in the back of classrooms at school and placed in the last row for group pictures. Noticeably taller than her peers, Apolonio always felt different. At 14, she finally found out why.
It was when she grew taller than her older brother that her concerned mother, Jovie, took her to a doctor in their hometown of Pasig City in the Philippines. The physician suspected Marfan syndrome — a rare genetic disorder that affects the connective tissue and can have an impact on many body systems, including the heart and blood vessels, eyes, skin and skeleton. Physical traits include a tall, slender build, a narrow face, loose joints and spinal abnormalities
Even after the diagnosis was confirmed, Apolonio had little more than a label for her symptoms. "I didn't understand what Marfan syndrome was or what to do about it," she says.

This is one of the most common scenario in patients with Marfan Syndrome. See further information at http://www.marfan.org/

Mother aged more than 35

Is is safe to be pregnant after 35?
While advances in medical care can help women over age 35 have safer pregnancies than in the past, health complications for this age group are higher than for younger women. If you have decided to delay having a child, you should understand the risks associated with this so you can take precautions to minimize risks and improve your chances for a healthy pregnancy and child.


Do I Have a Greater Risk of Having a Child With a Birth Defect if I'm Over 35?
The risk of giving birth to a child with a birth defect does increase as the mother's age increases. This is probably due to abnormal division of the egg, called nondisjunction. The traditional age at which a woman is considered to be at high risk for chromosomal abnormalities is 35. Approximately 1 in 1,400 babies born from women in their 20's have Down syndrome; it increases to 1 in 100 babies born with Down syndrome from women in their 40's.

My project (6)

…to regulate trafflicking…
trafficking --> processing posttranslational modification of proteins, particularly secretory proteins and proteins targeted for membranes or specific cellular locations.

Source: http://www.biology-online.org/dictionary/Trafficking

My project (5)

…ATP 7B…

*606882

ATPase, Cu(2+)-TRANSPORTING, BETA POLYPEPTIDE; ATP7B
Gene map locus 13q14.3-q21
DESCRIPTION
The ATP7B gene encodes a polypeptide that acts as a membrane copper-transport protein.


CLONING
On YACs from the 13q14.3 region, Bull et al. (1993) identified a sequence similar to that coding for the proposed copper-binding regions of the putative ATPase gene defective in Menkes disease (MNK; 309400). They showed that this sequence forms part of a P-type ATPase gene that is very similar to MNK, with 6 putative metal-binding regions similar to those found in prokaryotic heavy metal transporters. The gene, designated ATP7B, is expressed in liver and kidney, and was found to lie within a 300-kb region likely to include the Wilson disease locus (WND). The identity between MNK and the newly identified ATP7B gene was 78% in the transduction region, 89% in the channel/phosphorylation regions, and 79% in the ATP-binding region. The predicted length of the gene product was 1,411 amino acids for ATP7B compared with 1,500 amino acids for MNK. The overall identity between the two was 57%.
Tanzi et al. (1993) used consensus DNA sequences for heavy metal binding motifs to identify homologous cDNA clones. One of these was mapped by PCR amplification and Southern blotting to contiguous YAC and cosmid clones that span the WND locus at chromosome 13q14.3. The cDNA detected a 7.5-kb RNA transcript expressed most strongly in liver and brain. Sequence analysis indicated several membrane-spanning domains, an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least 2 putative copper-binding sites. The deduced protein showed 62% amino acid homology to the Menkes disease gene.
Yang et al. (1997) stated that the full-length ATP7B protein contains 1,465 amino acids. They cloned a splice variant of ATP7B lacking exons 6, 7, 8, and 12 from a human brain cDNA library. The deduced protein contains 1,258 amino acids. Immunofluorescence localization and fractionation of a hepatoma cell line revealed that the full-length protein was associated with the Golgi apparatus and the shorter isoform was cytosolic. Full-length ATP7B did not redistribute in response to elevated copper levels, and it did not associate with the plasma membrane.
Source: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606882

My project (4)

…ATP 7B…

*606882

ATPase, Cu(2+)-TRANSPORTING, BETA POLYPEPTIDE; ATP7B
Gene map locus 13q14.3-q21.1
DESCRIPTION
The ATP7B gene encodes a polypeptide that acts as a membrane copper-transport protein.
CLONING
On YACs from the 13q14.3 region, Bull et al. (1993) identified a sequence similar to that coding for the proposed copper-binding regions of the putative ATPase gene defective in Menkes disease (MNK; 309400). They showed that this sequence forms part of a P-type ATPase gene that is very similar to MNK, with 6 putative metal-binding regions similar to those found in prokaryotic heavy metal transporters. The gene, designated ATP7B, is expressed in liver and kidney, and was found to lie within a 300-kb region likely to include the Wilson disease locus (WND). The identity between MNK and the newly identified ATP7B gene was 78% in the transduction region, 89% in the channel/phosphorylation regions, and 79% in the ATP-binding region. The predicted length of the gene product was 1,411 amino acids for ATP7B compared with 1,500 amino acids for MNK. The overall identity between the two was 57%.
Tanzi et al. (1993) used consensus DNA sequences for heavy metal binding motifs to identify homologous cDNA clones. One of these was mapped by PCR amplification and Southern blotting to contiguous YAC and cosmid clones that span the WND locus at chromosome 13q14.3. The cDNA detected a 7.5-kb RNA transcript expressed most strongly in liver and brain. Sequence analysis indicated several membrane-spanning domains, an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least 2 putative copper-binding sites. The deduced protein showed 62% amino acid homology to the Menkes disease gene.
Yang et al. (1997) stated that the full-length ATP7B protein contains 1,465 amino acids. They cloned a splice variant of ATP7B lacking exons 6, 7, 8, and 12 from a human brain cDNA library. The deduced protein contains 1,258 amino acids. Immunofluorescence localization and fractionation of a hepatoma cell line revealed that the full-length protein was associated with the Golgi apparatus and the shorter isoform was cytosolic. Full-length ATP7B did not redistribute in response to elevated copper levels, and it did not associate with the plasma membrane.
Source: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606882

My project (3)

…ATP 7A and…
*300011
ATPase, Cu(2+)-TRANSPORTING, ALPHA POLYPEPTIDE; ATP7A
Gene map locus Xq12-q13
The ATP7A gene was cloned as a candidate for the site of mutations causing Menkes disease (MNK; 309400) by 3 independent groups (Vulpe et al., 1993; Chelly et al., 1993; Mercer et al., 1993). By a database search of the predicted sequence, Vulpe et al. (1993) found strong homology to P-type ATPases, a family of integral membrane proteins that use an aspartylphosphate intermediate to transport cations across membranes. The protein was found to have the characteristics of a copper-binding protein. Northern blot analysis showed that the mRNA of the gene, which was symbolized 'MNK' before its precise nature was known, is present in a variety of cell types and tissues, except liver, in which expression is reduced or absent. The findings were consistent with the clinical observation that the liver is largely unaffected in Menkes disease and fails to accumulate excess copper.
Levinson et al. (1994) and Mercer et al. (1994) isolated the mouse homolog of the Menkes disease gene. The mouse protein shows 89% identity to the human protein, and both proteins contain 8 transmembrane domains.

GENE STRUCTURE
Tumer et al. (1995) determined that the ATP7A gene spans about 150 kb of genomic DNA and contains 23 exons. The ATG start codon is in the second exon. The ATP7A and ATP7B (606882) genes showed strikingly similar exonic structures, with almost identical structures starting from the fifth metal-binding domain, suggesting the presence of a common ancestor encoding 1, and possibly 2, metal-binding domains in addition to the ATPase 'core.'
Dierick et al. (1995) showed that the ATP7A gene contains 23 exons distributed over approximately 140 kb of genomic DNA. The authors showed that exon 10 is alternatively spliced. They found that the structures of the ATP7A and ATP7B genes are similar in the 3-prime two-thirds region, consistent with their common evolutionary ancestry.

Source: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=300011

My project (2)



….proteins that interact with…
Protein-protein interactions refer to the association of protein molecules and the study of these associations from the perspective of biochemistry, signal transduction and networks.


My project (1)

Identification of proteins….
Basics of protein identification are simple: Proteins are digested and the resulting peptides are analyzed by mass spectrometers to obtain their mass data. There are three different types of MS data that can be used for database search. They are
(1) molecular weights of peptides that can be used for Peptide Mass Mapping,
(2) combination of mass data and partial amino acid sequence that can be used for Sequence Tag, and
(3) tandem mass spectrometry data (uninterpreted) that are used for MS/MS fragmentation ion search.
Source: http://msf.ucdavis.edu/ms_protein_id.html

RNA isolation protocol (1)

RNA isolation by the rapid Guanidinium method
Materials

Mononuclear cell pellet isolated from 1 to 2 ml bone marrow or 5 ml whole blood
HBSS without Ca or Mg
RNA isolation solution I (25 g guanidinium thiocyanate (4 M final), 29.3 ml H2O, 1.76 ml 0.75 M sodium citrate, pH7.0 (25 mM final) , 2.64 ml 10% (w/v) N-lauroylsarcosine (0.5% final) dissolve at 65 degree celcius, store at room temperature (stable > or equal 3 months)
Do not inhale quanidinium thiocyanate and wear gloves when handling it, Do not expose guanidinium thiocyanate to acid conditions, because this may produce cyanide gas.
2 M sodium acetate, pH 4
Buffered phenol
24:1 (v/v) chloroform/isoamyl alcohol
100% and 70% (v/v) ethanol
RNA isolation solution II (10 ml RNA isolation solution I, 72 microlitre 2-mercaptoethanol (0.1 M final) Make fresh before each extraction)
DEPC-treated H2O

DNA isolation protocol (1)

Isolation of Genomic DNA
DNA isolation from whole blood
Materials
10 ml fresh or thawed frozen whole blood
NKM buffer, 4 degree celcius
Resuspension buffer
10 X TEN solution
2 mg/ml proteinase K
10% (w/v) SDS
Buffered phenol
25:24:1 (v/v) phenol/chloroform/isoamyl alcohol
24:1 (v/v) chloroform/isoamyl alcohol
TE buffer, pH 8.0
Dailysis buffer
Refrigerated centrifuge
Orbital shaker
Dialysis tubing (MWCO 50000)
1.5 ml storage vials

Benefits, limitations and risks of genetic testing

Benefits
1. test results may lead to institution of timely and effective treatment or management.
2. test results may predict disease rognosis
3. test results may influence personal and reproductive decision-making
4. testing can predict eventual disease in the absence of disease symptoms
5. psychological benefits
. ability to btain societal benefits or support after confirmation of a diagnosis

Limitation
1. There may be no clinical test available
2. There may be no interventions to treat or prevent the condition
3. testing may be available at only few select labs or genetic centers
4. test interpretation may depend on other family members being tested.
5. some conditions are caused by many different mutations in a single gene (allelic heterogeneity), not all of which are detected by a particular test
6. There is the possibility that a given condition is caused by mutations in more than one gene (locus heterogeneity).
7. A negative test result does not necessarily eliminate the disorder in the differential diagnosis
8. A postive test result does not guarantee that the patient will develop the condition.
9.testing may yield indeterminate rsults
10. Tests or screens may have low sensitivity or specificity.

Risks
1. Test result may identify other at-risk family members without their consent.
2. Test results ay affect family integrity, dynamics and relationships
3. Testing can predict eventual disease in the absence of disease symptoms.
4. Testing may yield indeterminate results.
5. Genetic information is potentially stigmatization
6. Genetic information can potentially lead to discrimination.
7. Test results may cause psychological effects, including anger guilt, decreased self-worth or depression.

What is the genetic test?

A genetic test is a test that involves the analysis of chromosomes, genes and/or gene products (e.g. proteins or enzymes) to determine whether a genetic alteration related to a specific disease or condition is present.



(Secretary's Advisory Committee on Genetic Testing, 2002.)



What is the difference between genetic screening and genetic testing?
Genetic screening is used when your patient:
-Has no signs or symptoms
-Has no clinically significant family history
-Belongs to a certain population (such as a racial or ethnic group) that may be at greater risk for certain disorders or traits.
Genetic screening is not diagnostic; further testing is needed to confirm, make or predict the diagnosis of a condition. Examples of genetic screening are: newborn screening for phenylketonuria and carrier screening for Tay-Sachs disease and (although not currently the standard of care) population screening for hereditary hemochromatosis.



Genetic testing is used when your patient has:
-Clinically significant signs and/or symptoms
-A clinically significant family history
-Positive genetic screen results
Genetic testing can diagnose or predict the likelihood of a genetic condition. Examples of genetic testing are: diagnostic testing for Fragile X syndrome in a child with mental retardation, prenatal diagnostic testing for Down syndrome by amniocentesis, and presymptomatic testing for Huntington disease in an individual with a family history of HD.

History of genetics


Father of Medical Genetics
Victor Almon Mckusick
since 1912
Professor of Medicine at
John Hopkins Hospital,
Baltimore, MD, USA
original author and remains chief editor of Mendelian Inheritance in Man (MIM) and its online counterpart Online Mendelian Inheritance in Man (OMIM), a database of heritable diseases and genes

History of genetics


Father of modern genetics
Gregor Johan Mendel (1822-1884)
Austrian priest

Genetic counseling

main elements of geneticc counseling
1. Diagnostics and clinical aspects
2. documentation of family and pedigree information
3. recognition of inheritance patterns and risk estiation
4. communication and empathy with those seen
5. information on available options and further measures
6. support in decision-making and for decisions made

An educational process that seeks to assist affected and/or at risk individuals to understand the nature of the genetic disorder, its transmission and the options open to them in management and family planning