Vol. 10: Winter, 1994
Nontraditional Inheritance
Uniparental Disomy and Genomic Imprinting
Uniparental disomy refers to the presence of two copies of a chromosome (or part of a chromosome) from one parent and none from the other. The first human example of uniparental disomy was discovered in 1988 in a child with cystic fibrosis and short stature. Spence and coworkers proved that the child had received two copies of the same chromosome 7 with a mutant CF gene from her carrier mother, and none from her noncarrier father. Subsequently, several additional disorders resulting from uniparental disomy of single genes or multiple genes (including whole chromosomes) have been reported.
The frequency with which uniparental disomy occurs is unknown, since if abnormal disease genes are not involved, its occurrence may go undetected. In the case of cystic fibrosis, one estimate is that 1/500 affected individuals may be due to maternal uniparental disomy. The recurrence risk of CF in subsequent offspring would be significantly lower in cases of uniparental disomy (probably <1%) than in the usual situation in which each parent is a heterozygous carrier of the abnormal CF gene, with a recurrence risk of 25% with each pregnancy. Hence, it is wise to do genetic studies on both parents to be sure they are both carriers in order to provide the most accurate recurrence risk information.
A second and more readily detectable adverse outcome of uniparental disomy is the consequence of a newly recognized phenomenon called genetic or genomic imprinting. This term refers to the differential expression of genetic traits depending on whether the trait has been inherited from a mother or a father. Another way to think of genomic imprinting is as "parent of origin differences" in the expression of inherited traits.
Most regions of the genome are converted to gene products equally from the maternally and paternally derived members of a chromosome pair. For a few specific regions, however, this is not true, and the genetic information in a portion of certain chromosomes is inactivated when inherited from one sex parent but not when inherited from the other.
In these so-called imprinted regions, only one copy of the genes is transcribed, the other remaining genetically silent (at least in somatic cells). Scientists have recognized this process in plants and lower animals as well as in one of the two X chromosomes in females for several years, but have only recently detected it as a cause of human disease.
The first recognized example of such human abnormality resulting from the presence of uniparental disomy of an imprinted part of the genome was in Prader-Willi syndrome (PWS). This well known disorder is a multiple congenital anomaly/mental retardation syndrome characterized by infantile hypotonia, feeding problems and failure to thrive, dysmorphia and hypogonadism followed by obesity, mental insufficiency and short stature. Approximately 70% of affected individuals have a small deletion of the long arm of chromosome 15, always occurring in the paternally-derived chromosome 15.
The remaining 30% of patients have maternal uniparental disomy for chromosome 15. That is, they have two otherwise normal copies of maternal chromosome 15 and no paternal 15. Thus, Prader-Willi syndrome results from the absence of the paternal contribution to this region, which is genetically active and necessary for normal development, whether by deletion or maternal disomy. The two maternally-derived 15 chromosomes may be the same (the result of duplication of one 15, called isodisomy), different (the result of inheritance of the two different maternal 15s, called heterodisomv), or, most commonly, a combination of the two maternal chromosomes due to recombination. In all of these scenarios, the chromosomes themselves are completely structurally normal.
While the mechanism(s) leading to uniparental disomy 15 have not yet been fully delineated, there is evidence for an initial trisomy 15 conception, followed by chromosome loss. Specifically, there have been case reports of trisomy 15 found on chorionic villus sampling at 10"-1"1 weeks gestation, followed by amniocentesis at 16"-1"8 weeks documenting a viable fetus with two 15 chromosomes, and the resulting child having Prader-Willi syndrome on the basis of maternal uniparental disomy. This suggests non-dysjunction as a common mechanism for uniparental disomy which is supported by the observation of an advanced maternal age effect in cases of Prader-Willi syndrome due to maternal disomy, but not for those due to paternal interstitial deletion of 15q.
Uniparental maternal disomy for chromosome 15 is thought to cause Prader-Willi syndrome because there is absence of needed paternally contributed genes in the critical PWS region (del 15q11-q13). The paternal contribution is hypothesized to be necessary because the homologous maternally derived genes are inactivated or imprinted (perhaps by methylation).
Genetic imprinting thus appears to be a form of regulation of the expression of inherited genetic information. Evidence for the existence of genetic imprinting has also come from both animal and human studies. Mice developed by transgenic experiments so that they have only either maternally derived or paternally derived genes are phenotypically different. Those with only paternally derived genes have relatively normal development of membranes and placentas, but very poor development of embryonic structures. In contrast, those with only maternally derived genes have relatively good embryonic development but poor membranes and placentas. Both types of mice are non-viable.
These experiments demonstrate that both maternally and paternally derived genetic material is required for normal development, and that the contributions produce different effects. Human triploid fetuses, which have three rather than the normal two sets of haploid chromosomes, show analogous effects. Those with two paternal and one maternal chromosome set have large cystic placentas and poorly developed fetuses, whereas those with two maternal and one paternal chromosome set have very small placenta and usually result in miscarriage due to placental insufficiency. Again, a complement of both maternal and paternal contributions is required for normal development.
From this discussion, it follows that the phenomenon of uniparental disomy allows researchers to pinpoint which parts of the genome are imprinted. Mouse studies suggest that 10%-25% of the mouse genome is imprinted, but human data are still incomplete. As discussed above, the classic example of human genomic imprinting can be seen in Prader-Willi syndrome.
Interestingly, a very different disorder called Angelman syndrome also involves imprinting of the same chromosome region - only in Angelman syndrome the maternal contribution of the critical region is missing. The terminology used to describe the role of imprinting in these two disorders is somewhat confusing but goes as follows.
It is hypothesized that the critical genetic region which determines Prader-Willi syndrome is maternally imprinted ( i.e. inactivated when inherited from the mother), whereas the critical region which determines Angelman syndrome is paternally imprinted (i.e. inactivated when inherited from the father). Both disorders result when the expected active genetic contribution from one parent is missing, either by deletion or uniparental disomy.
Interestingly, a number of human congenital tumors show evidence of genomic imprinting. For example, in cells from Wilms' tumor, loss of the maternal chromosome 11 is common. This suggests that the maternal chromosome 11 has a tumor suppresser role not present on the paternal 11. This phenomenon in relation to cancer is referred to as "loss of heterozygosity".
Uniparental disomy and genomic imprinting should be suspected by alert clinicians when a patient or pedigree appears atypical. For example, the child described above with cystic fibrosis due to maternal uniparental disomy for chromosome 7 had marked short stature, possibly due to absence of needed paternal chromosome 7 material. One can also imagine a parent and child both affected by a recessive disorder, due to uniparental disomy. It may be that uniparental disomy is the cause of some syndromes of unknown etiology and of some conditions of intrauterine overgrowth or undergrowth whose cause is unknown.
The Genetic Drift Newsletter is not copyrighted. Readers are free to duplicate all or parts of its contents. The Genetic Drift Newsletter is published semiannually by the Mountain States Regional Genetic Services Network for associates & those interested in Human Genetics. In accordance with accepted publication standards, we request acknowledgement in print of any article reproduced in another publication. The views expressed in the newsletter do not necessarily reflect local, state, or federal policy. For additional information, contact Carol Clericuzio, M.D., Editor, Department of Pediatrics, The University of New Mexico, Albuquerque, NM, 87131
Nontraditional Inheritance: Table of Contents
Mosaicism
Mitochondrial Inheritance
Uniparental Disomy and Genomic Imprinting
Triplet Repeat Disorders
Additional Reading
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