Genomic Imprinting

Genomic Imprinting Table 4-2. Some Examples of Diseases in Which There is Locus Heterogeneity Disease Description Chromosomes on which known loci are located Retinitis pigmentosa

Progressive retinopathy and loss of vision More than 20 chromosome (see Chapter 8) regions identified

Osteogenesis imperfecta

Brittle bone disease

7, 17

Charcot-Marie-Tooth disease

Peripheral neuropathy

1, 5, 8, 10, 11, 17, 19, X

Familial Alzheimer disease Progressive dementia

1, 10, 12, 14, 19, 21

Familial melanoma

Autosomal dominant melanoma (skin cancer)

1, 9

Hereditary nonpolyposis colorectal cancer

Autosomal dominant colorectal cancer

2p, 2q, 3, 7

Autosomal dominant breast Predisposition to early-onset breast and cancer ovarian cancer

13, 17

Tuberous sclerosis

Seizures, facial angiofibromas, hypopigmented macules, mental retardation, multiple hamartomas

9, 16

Adult polycystic kidney disease

Accumulation of renal cysts leading to kidney failure

4, 16

Mendel's experimental work with garden peas established that the phenotype is the same whether a given allele is inherited from the mother or the father. Indeed, this principle has been part of the central dogma of genetics. Recently, however, it has become increasingly apparent that this principle does not always hold. A striking example is provided by a deletion of 3 to 4 million base pairs (Mb) on the long arm of chromosome 15. When this deletion is inherited from the father, the child manifests a disease known as Prader-Willi syndrome. The disease phenotype includes short stature, hypotonia (poor muscle tone), small hands and feet, obesity, mild to moderate mental retardation, and hypogonadism (Fig. 4-20A). When the deletion is inherited from the mother, the child develops Angelman syndrome, which is characterized by severe mental retardation, seizures, and an ataxic gait (Fig. 4-20B). Both diseases are seen in about 1 of every 15,000 individuals, and in both about 70% of the cases are caused by chromosome deletions. In most instances, the deletions that cause Prader-Willi and Angelman syndromes are microscopically indistinguishable. What could cause these differences? The 3- to 4-Mb portion of chromosome 15 that is deleted in both syndromes is known as the "critical region." Within this region several genes are transcriptionally active only on the chromosome inherited from the father, and they are inactive on the chromosome inherited from the mother. Similarly, other genes are transcriptionally active only on the chromosome inherited from the mother and are inactive on the chromosome inherited from the father. Thus, there are several genes in the critical region that are active on only one chromosome (Fig. 4-20C). If the single active copy of one of these genes is lost through a chromosome deletion, then no gene product is produced at all, and disease results. The differential activation of genes, depending on the parent from which they are inherited, is known as genomic imprinting. The transcriptionally inactive genes are said to be "imprinted."

Figure 4.20 Illustration of the effect of imprinting on chromosome 15 deletions. A, Inheritance of the deletion from the father produces Prader-Willi syndrome (note the inverted V-shaped upper lip, small hands, and truncal obesity). B, Inheritance of the deletion from the mother produces Angelman syndrome (note the characteristic posture). C, Pedigrees illustrating the inheritance pattern of this deletion and the activation status of genes in the critical region. AS, Angelman syndrome; PWS, Prader-Willi syndrome

Molecular analysis using many of the tools and techniques outlined in Chapter 3 (microsatellite polymorphisms, cloning, and DNA sequencing) has identified several specific genes in the critical region of chromosome 15. The Angelman syndrome gene encodes a protein involved in ubiquitinmediated protein degradation during brain development (consistent with the mental retardation and ataxia observed in this disorder). In brain tissue, this gene is active only on the chromosome

inherited from the mother; thus, a maternally inherited deletion removes the single active copy of this gene. Several genes appear to be involved in Prader-Willi syndrome, and they are active only on the chromosome inherited from the father. One of these genes, SNRPN, encodes a small nuclear riboprotein that is expressed in the brain. Several mechanisms in addition to chromosome deletions can cause Prader-Willi and Angelman syndrome. One of these is uniparental disomy, a condition in which the individual inherits two copies of a chromosome from one parent and none from the other (see Chapter 6 for further discussion). When two copies of the maternal chromosome 15 are inherited, Prader-Willi syndrome results because no active paternal genes are present in the critical region. Conversely, disomy of the paternal chromosome 15 produces Angelman syndrome. Point mutations in the identified Angelman syndrome gene can also produce disease. Finally, about 1% of cases of Prader-Willi syndrome result from a small deletion of the region that contains an imprinting center on chromosome 15. This is the DNA sequence that apparently helps to set and reset the imprint itself. Box 4-1 presents clinical issues of Prader-Willi syndrome from the perspective of a patient's family. BOX 4.1 A Mother's Perspective of Prader-Willi Syndrome We have a 3 1/2-year-old son, John, who has Prader-Willi syndrome. Months before John was born, we were concerned about his well-being because he wasn't as active in utero as his older siblings had been. At the first sight of John, the doctors suspected that things "weren't quite right." John opened his eyes but made no other movements. He couldn't adequately suck, he required supplemental oxygen, and he was "puffy." He remained hospitalized for nearly 3 weeks. The next 3 years were filled with visits to occupational therapists, physical therapists, home health care aides, early childhood service providers, and speech therapists. From the day John was born, we searched diligently for a diagnosis. His father insisted that we need only love and help him. However, I wanted specifics on how to help him and knowledge from other parents who might have traveled a similar path. After extensive testing and three "chromosome checks," John was diagnosed with Prader-Willi syndrome (PWS). We were glad to be provided with some direction and decided that we would deal with further challenges as they came upon us. We used what we learned about PWS to get started helping John reach his potential. We were not going to worry about all the potential problems John could have because of his PWS. John attends a special education preschool at the local elementary school 4 days a week. The bus ride takes about 5 minutes, but it is long enough for John to very much anticipate it each day. If he is ill, we have to tell him that the bus is broken. He attends a Sunday school class with children of a similar age. He misbehaves by saying "hi" and "bye" very loudly to each participant. He receives speech therapy once a week, and I spend at least 30 minutes each day with John, practicing speech, cognitive, and play skills. John has not yet experienced the feeding difficulties commonly observed in children with PWS. However, excessive eating and weight gain are more common in older children with PWS. Compared with other 3-year-old children, John struggles with speech and motor developmental milestones. Yet, he loves to play with his siblings and their friends and to look at books. In fact, we struggle to keep people from doing too many things for John because they might prevent him from attaining the same goal independently. We feel very privileged to have him in our family.

Our expectations for John are that he achieves everything that is possible for him plus a little bit more. Indeed, some of his care providers are already impressed with his capabilities. I hope that his success is partly a result of the care and support that we have given to him. Moreover, I hope that John continues to overcome the daily challenges that face him. page 79 page 80 A second example of imprinting in the human is given by Beckwith-Wiedemann syndrome, a disorder that involves large size for gestational age, large tongue, omphalocele (an abdominal wall defect), and a predisposition to Wilms tumor, a kidney cancer (see Chapter 14). As with Angelman syndrome, a minority of Beckwith-Wiedemann syndrome cases are caused by the inheritance of two copies of a chromosome from the father and no copy of the chromosome from the mother (uniparental disomy, in this case affecting chromosome 11). Some genes on chromosome 11 are imprinted, including insulin-like growth factor 2 (IGF2). This gene is imprinted (inactive) on the maternally derived chromosome and active only on the paternal chromosome. Normally, then, an individual has only one active copy of this gene. When two copies of the paternal chromosome are inherited, the active IGF2 gene is present in double dose. Two active copies can also result from a loss of the maternal imprint, activating the maternally inherited gene. It is thought that increased levels of the growth factor gene lead to the overgrowth features of Beckwith-Wiedemann syndrome and to Wilms tumor. In contrast to Prader-Willi and Angelman syndromes, which are produced by a missing gene product, Beckwith-Wiedemann syndrome is caused, at least in part, by overexpression of a gene product. www The molecular basis of imprinting remains unclear. In the genes known to be imprinted in mice or humans, of which there are now about 80, there is a strong association between methylation and transcriptional inactivation. The attachment of methyl groups to DNA may inhibit the binding of proteins that promote transcription. It is not yet known, however, whether methylation is the primary imprinting signal or whether it serves merely to maintain the imprinting signal once it has been established by other mechanisms (e.g., histone hypoacetylation and alteration in chromatin structure). ▪ Some disease genes may be expressed differently when inherited from one sex versus the other. This is genomic imprinting. It is associated with, and possibly caused by, methylation of DNA.