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Chromosome Translocation, Recombination, and Nondisjunction

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Chromosome Translocation, Recombination, and Nondisjunction Am. J. Hum. Genet. 58:1008-1016, 1996 The Impact of Imprinting: Prader-Willi Syndrome Resulting from Chromosome Translocation, Recombination, and Nondisjunction SuEllen Toth-Fejel,'"2 Susan Olson,",2 Kristine Gunter,'2' Franklin Quan," 3'4 Jan Wolford,3 Bradley W. Popovich,"3'4 and R. Ellen Magenis1,2 'Department of Molecular and Medical Genetics, 2Clinical and Research Cytogenetics Laboratories, and 3DNA Diagnostic Laboratory, Oregon Health Sciences University; and 4Shriners Hospital for Crippled Children, Portland Summary Several genetic mechanisms are responsible for the devel- Prader-Willi syndrome (PWS) is most often the result of opment of PWS. The majority (75%) of patients carry a deletion of bands qll.2-q13 of the paternally derived a deletion of the paternally derived chromosome i5qi1 - chromosome 15, but it also occurs either because of q13 (Ledbetter et al. 1981; Butler and Palmer 1983), maternal uniparental disomy (UPD) of this region or, with most nondeletion PWS patients having maternal rarely, from a methylation imprinting defect. A signifi- uniparental disomy (UPD) of chromosome 15 (Nicholls cant number of cases are due to structural rearrange- 1994). A small number of chromosomally normal pa- ments of the pericentromeric region of chromosome 15. tients carry an imprinting defect (Reis et al. 1994). PWS We report two cases of PWS with UPD in which there may be the clinical outcome of any chromosome 15 was a meiosis I nondisjunction error involving an altered structural change in which there has been a physical or chromosome 15 produced by both a translocation event functional loss of genetic material in the imprinted PWS between the heteromorphic satellite regions of chromo- critical region. somes 14 and 15 and recombination. In both cases, high- The PWS critical region is located in a region of - 3 - resolution banding of the long arm was normal, and 5 Mb (Donlon et al. 1986; Mutirangura et al. 1993) of FISH of probes D15S11, SNRPN, D15S10, and proximal chromosome 15. By virtue of (a) the fact that GABRB3 indicated no loss of this material. Chromo- only the paternal allele of the small nuclear ribonucleo- some heteromorphism analysis showed that each patient protein-associated polypeptide SmN (SNRPN) gene is had maternal heterodisomy of the chromosome 15 short expressed, (b) its map location of 15qi1-12 within the arm, whereas PCR of microsatellites demonstrated al- smallest region of deletion overlap for PWS (Ozqelik et lele-specific maternal isodisomy and heterodisomy of the al. 1992), (c) parent-specific differential DNA methyla- long arm. SNRPN gene methylation analysis revealed tion (Glenn et al. 1993, 1994; Sutcliff et al. 1994), and only a maternal imprint in both patients. We suggest (d) the predominant expression of this gene in neuronal that the chromosome structural rearrangements, com- tissue (McAllister et al. 1988), the SNRPN gene is con- bined with recombination in these patients, disrupted sidered a primary candidate gene for PWS. normal segregation of an imprinted region, resulting in Although a maternal age effect has been known since uniparental disomy and PWS. 1933 (Penrose 1933), the sequence of events that inter- fere with proper segregation, which presumably result initially in trisomy and then in UPD, are unknown. Non- disjunction is mostly attributable to maternal errors at Introduction the first meiotic division (i.e., MI) (Magenis and Cham- Prader-Willi syndrome (PWS) is an autosomal disorder berlin 1981; Polani 1981) and are associated with ad- characterized by neonatal/infantile hypotonia, mental vanced maternal age. An increase of nondisjunction is retardation, short stature, small hands and feet, hypogo- associated, as well, with chromosome structural rear- nadism, obesity, and hyperphagia (Prader et al. 1956). rangements, including Robertsonian translocations (Cattanach and Moseley 1973; Miller 1981). If proper meiotic segregation is dependent on timely resolution of Received March 24, 1995; accepted for publication February 22, chiasmata and/or the proper binding of chromosome- 1996. specific spindle fibers to centromeres and their associated Address for correspondence and reprints: Dr. SuEllen Toth-Fejel, kinetochore-related proteins, then rearrangements of Department of Molecular and Medical Genetics, 707 Southwest pericentromeric or unstable regions of the genome may Gaines Road, CDRC 2251, Portland, OR 97201. to © 1996 by The American Society of Human Genetics. All rights reserved. disrupt normal disjunction and lead uniparental 0002-9297/96/5805-0013$02.00 disomy. 1008 Toth-Fejel et al.: Nondisjunction in Prader-Willi Syndrome 1009 sodes. Parental ages at the time of ME's birth were both 34 years. Case 2 (Patient DK) Patient DK was a 39-year-old male with PWS. His neonatal and early infancy history included hypotonia, hyporeflexia, feeding difficulty, and no crying. Esotro- pia, bilateral cryptorchidism, and clubfeet were noted. At DK's birth, his mother's age was 24 years and his father's age was 27 years. Although DK's weight is now fairly well controlled, he has had a history of accelerat- ing weight gain after age 1 year. PWS characteristics were evident; DK had narrow up-slanted palpebral fis- sures and a downturned mouth with a thin upper lip. His eye and hair color were dark; hands and feet were small even for his short stature (fig. 1B). Trilafon, pre- Figure 1 A, Patient ME at age 11 years. She has the PWS charac- teristic facial features of slight bitemporal narrowing, almond-shaped scribed to reduce DK's disruptive outbursts, was pre- eyes, and a downturned mouth. Note that her eye color and hair color sumably responsible for this patient's dystonia. are dark, consistent with UPD. B, Patient DK at age 39 years. This patient, too, has almond-shaped eyes, a downturned mouth, and brown High-Resolution Chromosome Banding, eyes and hair. He has short stature, as well as small hands and feet. Heteromorphism Analysis, and Parental Origin High-resolution chromosomes were prepared from peripheral blood lymphocytes, G-banded (Yunis and To further explore the mechanisms of recombination Chandler 1977), R-banded, (Schweizer 1980) and Q- and segregation in chromosome structural rearrange- banded (Caspersson et al. 1970). The chromosome 15 ments that lead to UPD, we have studied in depth, at origin was established by comparing parental and pa- the cytogenetic and molecular levels, two PWS patients tient Q-banded chromosome 15 heteromorphisms with complex rearrangements of chromosomes 14 and (Olson et al. 1986; Magenis et al. 1990). 15. FISH and special staining techniques were used to determine the presence or absence of chromosome mate- FISH rial, translocation breakpoints, and chromosomal ori- FISH studies were performed according to the gin. Molecular studies, including microsatellite poly- ONCOR protocol, with the following chromosome 15 morphism analysis and VNTR analysis, were used to probes: D15Z, which is specific for highly repeated cen- determine recombination and paternity, respectively. tromeric alphoid DNA; D15Z1, a probe that recognizes Parent-specific patterns of methylation in the SNRPN short repeats related to AATGG in "classical" satellite gene were examined to assess the imprinted nature of DNA located in pericentromeric heterochromatin; and the region 15q11-q13. the 15q11-q13 specific probes DiSS11, SNRPN, DiSS10, and GABRB3. Probes were labeled with digox- Cases, Material, and Methods igenin or biotin and were detected with FITC or rhoda- mine. Chromosomes were counterstained with DAPI or Case 1 (Patient ME) propidium iodide and were visualized on a Zeiss Axio- Patient ME, was an 11-year-old female diagnosed phot equipped with Zeiss FITC/PI and DAPI/FITC/ with PWS who had essentially all of the diagnostic fea- TEXAS RED filter sets. The number of chromatids with tures. Consistent with the major and minor criteria a signal were scored in -20 cells for each FISH proce- (Holm et al. 1993), she had neonatal/infantile hypoto- dure. nia, feeding problems, and failure to thrive in infancy, followed by rapid weight gain before the age of 5 years. Methylation Studies Her facial features included narrow bitemporal diame- Two micrograms ofperipheral lymphocyte DNA were ter, almond-shaped eyes, and downturned mouth. Nota- digested with XbaI and the methylation-sensitive en- ble were her dark eyes and hair color (fig. 1A). She had zyme NotI, were electrophoresed through 1.0% agarose short stature (Sth percentile). Her hands and feet were gels, and were transferred to Biodyne B membranes. small for height and age, the hands being narrow with Hybridizations were performed with a 600-bp NotI- straight ulnar borders. She showed moderate develop- EcoRI fragment that included the -1 exon of the mental delay, as well as hyperphagia and aggressive epi- SNRPN gene, which detects a 4.3-kb XbaI band from 1010 Am. J. Hum. Genet. 58:1008-1016, 1996 the methylated maternal allele and a 0.9-kb NotI band suggested a de novo translocation of the chromosome from the unmethylated paternal allele (probe graciously 14 short-arm satellite (fig. 3A, maternal chromosome c) provided by R. D. Nicholls, Case Western Reserve Uni- to the short-arm satellite region of chromosome 15 (fig. versity, Cleveland, and D. J. Driscoll, University of Flor- 3A, maternal chromosome h), with some apparent loss ida, Gainesville). of chromosome 14 stalk and satellite. FISH analysis showed no loss of any of the single-copy probes, PCR Determination of Chromosome Origin DiSS11, SNRPN, DiSS10, and GABRB3. Approxi- Origin studies were performed by examining chromo- mately 20 cells were examined for each probe. All cells some 15 microsatellite repeats by PCR analysis. Primers showed a probe signal on each chromatid of each homo- for the amplification of DiSS101, D15S102, D15S113, logue (as well as the identification probe signals) (fig. D15S87, DiSS11, GABRA5, GABRB3, and FES were 4A-D). In all cases, the single-copy probe annealed, as obtained from Research Genetics, Inc., and were used expected, to the translocation chromosome, indicating according to the manufacturer's instructions.
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