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Alternate Centromere Inactivation Ina Pseudodicentric (15;20)(Pter;Pter

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Alternate Centromere Inactivation Ina Pseudodicentric (15;20)(Pter;Pter J Med Genet: first published as 10.1136/jmg.26.10.626 on 1 October 1989. Downloaded from Journal of Medical Genetics 1989, 26, 626-630 Alternate centromere inactivation in a pseudodicentric (15;20)(pter;pter) associated with a progressive neurological disorder H RIVERA*t, 0 ZUFFARDI*t, P MARASCHIO*, A CAIULO*, C ANICHINI§, R SCARINCI§, AND R VIVARELLI§ From *Biologia Generale e Genetica Medica, Universita de Pavia; tCattedra di Biologia Generale, Facolta di Medicina, Universita di Firenze; and §Clinica Pediatrica, Universitai di Siena, Italy. SUMMARY A 13 year old male with a severe progressive neurological disorder was found to have a pseudodicentric chromosome resulting from a telomeric fusion l5p;20p. In lymphocytes, the centromeric constriction of the abnormal chromosome was always that of the chromosome 20, while in fibroblasts both centromeres were alternately constricted. Cd staining was positive only at the active centromere, but a weak anticentromere immunofluorescence was present at the inactive one. We suggest that centromere inactivation results from a modified conformation of the functional DNA sequences preventing normal binding to centromere specific proteins. We also postulate that the patient's disorder, reminiscent of a spongy glioneuronal dystrophy as seen in Alper's and Creutzfeldt-Jakob diseases, may be secondary to the presence of the pathogenic isoform of the prion protein encoded by a gene mapped to 20p12-3-pter. copyright. The concept of a non-functional or weak centromere The pregnancy was complicated by maternal hypo- was first advanced to explain the behaviour of a glycaemia in the sixth month. Delivery took place in dicentric wheat chromosome during cell division.' the 38th week with cephalic presentation; birth The term centromere inactivation was introduced weight was 2750 g. Because of severe perinatal later to account for comparable observations in hypoxia, the infant was kept in an incubator for http://jmg.bmj.com/ man2 and is currently used in mammalian cyto- 20 days. At three months of age, he had a genetics. Inactive centromeres behave as inert generalised febrile convulsion, which recurred one structures during cell division possibly as a conse- year later. Psychomotor development was reportedly quence of ineffective spindle attachment. This normal until three years when he suffered from functional inability is consistently correlated with a severe encephalitis-like illness with loss of con- negative Cd staining3 4 and, in most cases, with the sciousness for 10 days; afterwards, he was no longer absence of constriction in mid-metaphase, while the able to walk and talk and showed progressive centromere associated heterochromatin usually intellectual impairment. At that time, an EEG on September 23, 2021 by guest. Protected retains its staining properties. In most heterodicentric disclosed a disorganised pattern with diffuse par- chromosomes, the inactivation affects only one oxysms and mixtures of spikes and sharp waves. CT centromere in an apparently random manner. 6 We scan showed slight enlargement of the cerebral report on a heterodicentric chromosome exhibiting fissures and ventricular system. Other examinations, alternate centromere inactivation. such as muscle biopsy, plasma chromatography, lysosomal enzyme determinations, and skeletal Case report radiographs, yielded normal results. At 10 years, a fundoscopy showed pale papillae, some pigmentary The patient was born on 6.4.76 to a 35 year old, changes, and incipient capsular lens opacification. G3P1A1 mother and an unrelated 42 year old At 13 years, the patient was confined to a supine father. Both parents and the only sib are healthy. position and had axial hypotonia but hypertonic tetraparesis and increased deep tendon reflexes; tPresent address: Division de Genetica, Instituto Mexicano del Seguro Social. Ap Postal 1-3838, Guadalajara, Jalisco, Mexico. Babinsky sign was negative. He was unable to and Received for publication 29 March 1989. communicate and was incontinent. Hearing Accepted for publication 13 April 1989. vision were apparently preserved. Facial features 626 J Med Genet: first published as 10.1136/jmg.26.10.626 on 1 October 1989. Downloaded from Alternate centromere inactivation in a pseudodicentric (15;20)(pter;pter) 627 ., A., I '.F, . -.|| >~~~~~~~~~~~~,..... X*; - b v i *A2 0 4 4^ , /1 4 4 copyright. (; d A t \ ;-/ AO ---- s S FIG 1 The pseudodicentric 15;20. (a) High resolution G banding (the normal 15 is upside down). (b, c) The active No 15 centromere as identifed by C and DA-DAPI banding. (d, e, f) The active No 20 centromere as identified by Cd, C, and DA-DAPI banding. Also note the Ag-positive NOR in the abnormal chromosome. http://jmg.bmj.com/ were somewhat coarse and the tongue was protruding. Results A slower activity was observed in repeated EEGs. 45 with an Material and methods The patient had chromosomes abnormal chromosome resulting from an end to end fusion of Lymphocyte and skin fibroblast cultures were 15p;20p. This chromosome had only one primary prepared and processed by standard techniques. constriction, which, in lymphocytes, always corres- Chromosome preparations were processed for Q, ponded to the No 20 centromere, whereas in G, C, NOR, DA-DAPI, and high resolution7 fibroblasts both centromeres were alternately con- on September 23, 2021 by guest. Protected banding techniques. The centromeres were further stricted (fig 1, table). In one fibroblast, the chromo- characterised by the Cd8 and anticentromere some appeared as a true dicentric. The hetero- immunofluorescence9 staining techniques. Parental chromatin associated with either the suppressed or chromosomes were studied in blood lymphocytes active centromeres was C and DA-DAPI positive. with Q and NOR banding. The inactive No 15 centromere was Cd negative in lymphocytes and exhibited a weak fluorescence after antikinetochore staining in fibroblasts (fig 2). TABLE Patterns of active centromeres in lymphocytes and The smaller number of cells with the opposite fibroblasts identified by C or DA-DAPI banding. inactivation pattern prevented a similar character- isation of the suppressed No 20 centromere. The Active No 15 Active No 20 intercalary NOR was Ag positive in all of the 28 Lymphocytes 0 144 (100%) lymphocytes scored. The patient also had a mater- Fibroblasts 2n* 6 (7-9%) 70 (92 1%) nally inherited inv(9) and thus his karyotype is Fibroblasts4n 4 (12-5%) 28 (875%) 45,XY,inv(9)(pllql3)mat,-15,-20,+psu dic (15;20) *In one additional cell the chromosome appeared dicentric. (pter;pter). J Med Genet: first published as 10.1136/jmg.26.10.626 on 1 October 1989. Downloaded from 628 H Rivera et al FIG 2 A metaphase plate-after anticentromere immunofluorescence (left) and DA-DAPlstaining (right). Note the weak fluorescence at the inactive No 15 centromere. copyright. At the first and second passages 64 of 252 As to the mechanism of centromere inactivation, fibroblast metaphases (25.4%) were tetraploid, but a functional modification2 18 or a deletion'1 15 19 of at the seventh passage only three. of 31 cells were. critical DNA sequences have been proposed. In In 32 C banded tetraploid cells, both abnormal fact, a centromeric deletion was shown in a cell line chromosomes showed the same centromere in- of a patient with a terminal rearrangement 13p;20q.15 activation pattern. Nevertheless, the following points are in favour of a Parental karyotypes had no informative chromo- functional modification. (1) The common finding http://jmg.bmj.com/ some 15 polymorphisms. that an inactive centromere is C band positive Discussion suggests that deletions detectable by light microscopy do not usually occur. (2) It is hard to conceive the This abnormal chromosome appears to result from a concurrence of similar or identical deletions, telomeric fusion without visible material loss. It is especially if secondary to mechanical forces,15 in indeed a pseudodicentric with two centromere heterodicentric and multicentric chromosomes with inactivation patterns, the No 20 centromere being inactivation of two or more centromeres.102 20 predominantly active. We know of four other (3) The diverse amounts and presumably classes of on September 23, 2021 by guest. Protected heterodicentrics with alternate centromere inactiva- centromeric antigens detected by specific antibodies tion,'043 but whether such functional mosaicism on inactive centromeres9 21 22 could reflect different results from successive inactivation-reversion pro- degrees ofthe inactivation phenomenon, as suggested cesses or long enough persistence of a functionally by T C Hsu to Earnshaw and Migeon.2' (4) A dicentric chromosome to produce the distinct cell conspicuous cell to cell intraindividual variability lines is still uncertain.14 15 Although an irreversible of Y isodicentrics, ranging from a chromosome inactivation has been documented in one instance,16 with two active centromeres to a monocentric the finding in the same cell of pseudodicentrics with element,17 23 24 has been noted. different centromere inactivation patterns12 17 indi- Centromeric constituents of eukaryotic chromo- cates that a reversible process can also exist. Our somes have been conserved during evolution.25 26 case differs from the previous ones in the apparently By analogy with the well known centromeric DNA tissue limited differential centromere activity, but sequences of yeast, there may be repeats of a whether this is the result of sampling error or prototypical unit essential for spindle attachment in represents a genuine difference of potential signifi- higher organisms.27 In addition, satellite DNA cance remains open to question. seems to play a crucial role in the pairing of sister J Med Genet: first published as 10.1136/jmg.26.10.626 on 1 October 1989. Downloaded from Alternate centromere inactivation in a pseudodicentric (15;20) (pter;pter) 629 chromatids at the primary constriction. 28-30 Both A Caiulo is supported by Associazione Studio these functions are mediated by specific DNA- Malformazioni, Milano..The authors are grateful to protein interactions. Among the several centromeric Professors M Fraccaro and A Fois for critical proteins, the CENP-B antigen would be responsible reading of the manuscript.
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