Genetics of Prader Willi Syndrome

Table of contents:

Genetics of Prader Willi Syndrome:

Molecular pathology:

Since PWS was first described there were no gross or microscopic evidence, which proves the abnormality within any clinical aspects for the disorder. In 1976 Hawkey and Smithies noted that most of the cases of the translocation occurs in chromosome 15 in individuals with PWS. However in the following Robertsonian Translocation it was believe that no transcribed unit has been deleted from the chromosome, infect it was found that two chromosome have stuck together, losing only a small amount of the nucleoli synthesizing code from the DNA molecule. Further advances in human genetics describe the following possibilities for the occurrence of PWS:

De novo Deletion
Uniparental Disomy
Imprinting Errors

Chromosomal deletion: After 1970s with the help of prometaphase or high-resolution chromosome bending the above mentioned hint of chromosome 15 were analyzed by Ledbetter, Riccardi, Airhart, et al., 1981. They reported a deletion in sequence of chromosome 15 i.e. 15(q11-q13) in approximately 50% of the PWS individuals. When the parents were examined for the inherited probability they found none of the deletion in any side so it was assumed as a new mutation in or change in the offspring with PWS, which was further known as de novo deletion. De novo deletion happens due to either the malformation of nucleotide during nucleotide biosynthesis (i.e. de novo pathway) or malfunctioning of early DNA methylase (i.e. de novo methylase). An amino acid is important as a precursor in de novo pathway for example glycine which is important for formation of purines where as aspertate is important for formation of pyrimidines. On the other hand in de novo methylase malfunctioning of any methylases may inactivate the essential transcribing unit from the DNA molecule and may lead to a diseased phenotype in an individual. There are two form of methylases have been observed in mouse those are designated as Dnmt3A and Dnmt3B.

Recent studies on PWS indicated a 60-70% of patient shows deletion in the 15^th chromosome. Although the parental chromosome look normal in 1983 Butler and Palmer used chromosomal polymorphism to identify that the deletion in offspring were inherited from father, which were further proved by the help of advanced molecular genetic technology. Because both parental chromosomes had normal chromosome it assumed that the deletion must be occurred in sperm with new changes in a PWS child. The chromosome of PWS patients have been compared with normal individuals which is shown in figure (x) and (y)** respectively.

Uniparental Disomy: The reason why some people have normal chromosome and some with deletion came to know when Nicholls et al. used molecular genetic markers to study the 15q11-q13 region which was best in many ways to simple chromosomal analysis. Interestingly they concluded that in some cases of the PWS patients had two maternally derived chromosomes and no contribution from paternal chromosome (Nicholls, Knoll, Butter, et al., 1989) and the phenomena was known as uniparental disomy. It can be differentiated in two parts called uniparental isodisomy and uniparental hetero disomy as shown in figure (x)**. Isodisomy results due to the non-disjunction in meiosis 2 where as heterodisomy occurs by non-disjunction of chromosome in meiosis 1. It has been documented by Cassidy, Lai, Erickson, et al. in 1992 that in 10^th week of a PWS fetal embryo shows three no(s) of chromosome 15 which further tested after 16-18 weeks of embryo with a loss of one chromosome, and at time of birth the baby was observed with hypotonic and feeding problems.

Genetic Imprinting: The genetic findings in the case of PWS best are explained by a phenomenon called genetic imprinting. It describes a change in a gene by methylation, which results through differences in parental or maternal allele during early embryo. Specific sequences in each alleles, contributed by each parent and it acts on an alternative fashion due to the imprinting mechanism. This is the reason behind the behavioral changes of two alleles in zygote, it requires to be established specifically during each gamatogenesis. Imprinted genes some times and found in two different region which suggest that the imprinting mechanism may function over long distances. Deletion in a particular region of chromosome 15 may be inherited from the paternal origin which might be contributed from as methylated sequence from the grand mother to the father of the infected individual and never been reset. The lack of resetting procedure in the particular sequence further leads to a silent sequence, which gives rise to the symptoms of PWS. It is believe that the converse is true in 60-70% of Angelman Syndrome which is clinically very distinct disorder and very similar chromosomal deletion occurs on the region of chromosome 15(q11-q13), but this time the deletion occurs from the maternal side. Figure (x) shows a case of Angelman Syndrome**.

The above-mentioned origins of PWS indicate different proportion in affected individuals. (2)

Event Proportion of PWS

Deletion ~75%

Uniparental Disomy ~20%

Imprinting Errors ~2%

(2) Adapted from Human Molecular Genetics 3 (Strachan and Read)*

As far as PWS is concerned it is more complex because there is a deletion of huge transcripts, which has up to 460kb and 148 exons. The upstream axons (up to 10) codes for two proteins SNURF and SNRPN while the downstream intones encodes for snoRNAs, which may responsible for the symptoms of Prader Willi Syndrome. The downstream part of the transcript overlaps other gene named UBE3A on the other strand act as an anticancer RNA and prevents transcription of the following gene (Runte et al., 2001). Point mutation may be the major cause of these changes in a PWS individual.

Chromosome Region (15q11-q13):

After mid 1980s the advances in genetic techniques made possible to detect the q11-q13 region on 15^th chromosome, which is responsible for producing or preventing PWS and Angelman Syndrome. Studies on this region of chromosome 15 interestingly show 90% of PWS and Angelman Syndrome patients had deletion on the q11-q13 region. It has been also considered that these genetic disorders are different from each other but very close together (as shown in figure (x)**) on the following segment of 15q11-q13 and deletion of either part of the region leads to one of the disease between these two genetic disorders. It has also been observed the gene responsible for albinism* or genetic hypopigmentation, is present on the same segment of 15^th chromosome with different locus. However albinism* is not a part of either Angelman Syndrome or PWS and it is not imprinted, but deletion on the segment for either case of disorder some times observed with hypopigmentation.

In 1992 Buiting et al. isolated candidate genes from 15q11-q13 region, he observed four to five different MN7 genes spread over the causative region and may be related to the instability of chromosomal region which leads to the etiology of PWS and Angelman syndrome. Using methyl sensitive restriction enzyme and immobilization with southern blot with cDNA and genomes, it was estimated that PWS and AS individual have a distinct methylation pattern of the parental alleles in very conserved cDNA DN34 sequence (Driscoll et al., 1992). Next year Clyton and Smith used the same sequence DN34 and tested it for DNA methylation in two first cousin male who had AS and PWS respectively and concluded that the pattern of methylation varies according to the parent origin. The SNRPN gene was detected by RT-PCR and observed to be expressed in normal and AS individuals but not in PWS cases, which may cause defects in mRNA processing. Buiting et al. (2003) analyzed that 14% of concerned PWS patient were found with a deletion in the critical IC elements where as the percentage of AS was 9%. In 27% of patient he observed that in case of AS with no IC deletion must have imprinted defect gene from the maternal grandfather or grand mother however in case of PWS the imprinting defect was noted from paternal grand mother. One of the rare causes of PWS is balanced translocation affects paternal copy. A brake point cluster region has been defined as on SNURF-SNRPN gene which is disrupted by one of the unknown 3-prime exons of this gene. There are few more genes were found inactivated in the case of PWS patients for example snoRNA, IPW, and PAR1 which may contribute to the characteristics of PWS. (1)****

Recurrence Risk:

There is no theoretical evidence of recurrence in PWS within a family, which has siblings with either case of paternal or maternal deletion. Where is the possibility of more than one affected child could be at a negligible recurrence risk. In these following families there is a possibility of genetic imprinting, which may be caused by a single gene defect. Further studies of these families will evaluate some more information regarding PWS and its recurrence. Those people who have PWS without any deletion or disomy are at the high risk of recurrence however there is a very little information available to speculate the degree of risk. At this stage where a family, which has a PWS child, have less than 1% chance of having another affected child. In case of translocation the theoretical risk may become a bit higher, but there is no such recurrence has been documented. Individual with PWS may pass the 15q deletion to the next generation and if the individual is a male the recurrence risk may reach to 50% of getting an offspring with PWS symptoms. In case of female the similar risk would be found as an Angelman Syndrome. However there is no reported cases of children been found born to an individual with PWS as the infertility.

Genetic Counseling:

In case of PWS medical geneticists are the physicians who provide information regarding genetic disorders. Such professionals who are certified from the American Board of Medical Genetics or equivalent can provide families, the supportive information about the diagnosis, history, and outcomes of the defect. They describe the characteristics of disease, findings, genetic basis, recurrence risk and methods for prenatal diagnosis. The goal of genetic counseling is to assist families at the risk of genetic disorder.

Grasping unusual facts of PWS is a part of genetic counseling process, which assists the affected families with giving an idea about the disease and help people to understand the fact that the cause of disease is no body’s fault it is caused due to a chromosomal alteration, which can not be predicted. It is a complex process of getting genetic information from parent to child. Generally, it has been seen that people due to anxiety of hearing news of diagnosis preclude themselves from geneticist. This is the reason why the genetic counselors often requested to reiterate their assumption to prevent genetic errors. Genetic counseling is non-directive, family members do not emphasize on it because of their moral, ethical, religious and experimental background issues. Information provided about family support organization and appropriate management.

Contact : webmaster@welovelmc.com