Trisomy, Monosomy, Ring Chromosome 20p and Genetic Imprinting
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Chromosomal abnormalities involving the prion gene
Experimental recommendations
Trisomy in chromosome 20p
Ring trisomy in chromosome 20p
Monosomy in chromosome 20p
Chromosome 20 genetic imprinting

Chromosomal abnormalities involving the prion gene

22 Dec 98 webmaster
Numerous experiments have established prion gene dosage effects in transgenic rodents. One effect is more rapid onset of disease, which might be simply attributable to constitutive expression, more prion protein being made, and a mass-action effect driving a delicate equilibrium towards rogue conformation.

Trisomy, or partial trisomy, of chromosome 20 is not that rare. [The prion gene resides at chr 20p 12.17] Are these individuals at increased risk for nvCJD, sporadic CJD, and iatrogenic CJD, in the same sense high copy number rodents are at increased risk? Among sporadic CJD victims, is the age of onset earlier and progression more rapid with prion gene trisomics?

For trisomy of chromosme 21 [Downe's syndrome] and beta amyloid, the answers are yes: precocious dementia of Alzheimer type. Gene dosage effects are similar in yeast sup35 prion-like protein. It would be an interesting exercise to examine GG Glenner's compilation of 20 cross-beta congophilic diseases to see which others besides Alsheimer have an enhanced incidence in trisomy.

Prusiner's group did look in 1991 at trisomy 16 mouse, a Down's syndrome model, for scrapie susceptibility, finding modest reductions of onset (153 to 138 days) and age at death (170 to 140 days) in Ann Neurol. 1991 Jan;29(1):95-7. The region about APP on mouse chromosome 16 is maps syntenically to human chromosome 21q. This study could not attribute the effect to the extra copy of the APP gene per se. They seemed not to have pursued more relevent trisomy 2 in mouse or human trisomy 20.

Three copies of the prion gene have been acquired by a number of mechanisms, including balanced and unbalanced translocations and secondary nondisjunction, formation of small ring chromosomes, and recombination of a pericentric inversion. About 10% of the cases are de novo. When a fragile chromosome fragment is involved, instability may result in somatic mosaicism. In all cases, the prion gene regulatory region would accompany the extra gene and presumbly allow for normal transcription.

What happens when the prion gene is sequenced in the course of characterizing a case of CJD -- is karyotyping routinely done and how frequently has chr 20p trisomy been found? Regretably, no one seems to have ever looked at this though one suspicious case was found in 1989. PCR gives the researcher no idea how many copies of the gene are present; we are lucky if both alleles are determined even in familial CJD.

How common is trisomy, or partial trisomy, of chromosome 13 in cattle or sheep? Are these animals disproportionately represented in BSE or scrapie cases? Here less is known about trisomy frequency in general and zero is known about trisomy in connection with these TSE's. Medline shows nothing for sheep with (karyotyp* OR trisomy) AND scrapie'.

Monosomy, or partial monosomy, of chromosome 20p has also been observed and arises from similar mechanisms. Here, the effect is expected to be opposite: lower incidence of sporadic CJD, later onset, and slower progression.

Genetic imprinting is a vaguely similar to monosomy but with different sequelae. In this relatively newly discovered phenomenon (7 examples were known in mouse by 1995), one of the parental copies is preferentially expressed. This can be quite complex for genes with alternate splicing. The prion gene cannot exhibit absolute imprinting in vivo because in heterozygous familial CJD, both allele products are sometimes found in amyloid. Supposing that partial imprinting exists, some portion of the heterogeneity of CJD in different lineages or within the same family, might be attributed to this effect. Chromosome 2 of mouse has a whole imprinting region syntenic to human chromosome 20. While the boundaries and content are not precisely known, the imprinted genes are attributed to 20q13 (thus quite remote to 20p12 prion gene).

Most cases of chromosome 20 anomalies come to light in the first place because the affected individual has a broad spectrum of severe symptoms, that is, few studies begin with healthy individuals. When all of chromosome 20 is involved -- plus the individual has CJD -- these other problems would, one hopes, surely be noted in the clinical write-up of the CJD. However, statistically, even if trisomy have a 100x rate enhancement of sporadic CJD, so few individuals are involved that the resultant caseload could be quite small. The situation of partial trisomy is not so clear: in the extreme case of a small tandem duplication of 100kb of DNA containing the prion gene, there might not be any observable pleiotrophic effects.

Under these circumstances, it is essential that fluorescence in situ hybridization [FISH] studies be conducted on the 34 cases of nvCJD to determine if this contributes to early onset in a group that had, relatively speaking, unexceptional exposure to dietary BSE. More broadly, FISH should be conducted in sporadic CJD to determine whether extra gene copies are disproportionately present here as well. Comparable work is needed on chromosome 13 of sheep and cattle -- what is the point of breeding in a certain ORF allele if the real problem in susceptibility was linkage to supernumerary copies?

Trisomy, monosomy, ring chromosome 20p and genetic imprinting references

Alternate centromere inactivation in a pseudodicentric (15;20)(pter;pter) associated with a progressive neurological disorder.

J Med Genet 1989 Oct;26(10):626-30 
Rivera H, Zuffardi O, Maraschio P, Caiulo A, Anichini C, Scarinci R, Vivarelli R
A 13 year old male with a severe progressive neurological disorder was found to have a pseudodicentric chromosome resulting from a telomeric fusion 15p;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----pter.

Analysis of a whole arm translocation between chromosomes 18 and 20 using fluorescence in situ hybridization: detection of a break in the centromeric alpha-satellite sequences.

Hum Genet 1995 Mar;95(3):299-302 
Tumer Z, Berg A, Mikkelsen M
Using classical cytogenetic techniques, we detected a male patient with monosomy 18p/trisomy 20p, originating from a paternal reciprocal translocation of the short arms of chromosomes 18 and 20. To characterize the breakpoints further and to determine the centromeric origin of the chromosomes involved, we analyzed the metaphase chromosomes by fluorescence in situ hybridization using alpha-satellite DNA probes specific to chromosomes 18 and 20. With this approach, we showed that alpha-satellite centromeric fragments were involved in the translocation event and that the chromosome-18-specific centromeric sequences were split into two. Analysis of 14 family members from four generations revealed nine phenotypically normal individuals carrying this reciprocal translocation. These results suggest that breaks in alpha-satellite DNA fragments neither impair the centromeric function nor have clinical effects.

Duplication 20p identified via fluorescent in situ hybridization.

Am J Med Genet 1994 Apr 1;50(2):187-9 
LeChien KA, McPherson E, Estop AM
A 3-year-old girl is reported with dup (20p) resulting from 3:1 segregation of a de novo t(20;21). The proposita presented with minor anomalies, developmental delay, a clinical phenotype suggestive of 20p trisomy, and a karyotype with a 21p+ and an additional small marker chromosome. Conventional cytogenetic techniques were not informative for the identification of the origin of the extra material of chromosome 21p nor for the marker chromosome. The 21p+ and marker chromosomes were successfully characterized using fluorescent in situ hybridization (FISH).

Fluorescence in situ hybridization (FISH) of a whole-arm translocation involving chromosomes 18 and 20 with alpha-satellite DNA probes: detection of a centromeric DNA break?

Am J Med Genet 1992 Oct 1;44(3):340-4 
Cantu ES, Khan TA, Pai GS
Fluorescence in situ hybridization (FISH) with alpha-satellite DNA probes was used to study whole-arm chromosome translocation products in a family in which the propositus was shown to have a monosomy 18p/trisomy 20p imbalance. By this approach, we show that the chromosome 18 alpha-satellite DNA block is split into 2 smaller units, whereas the chromosome 20 breakpoint is not included within the alpha-satellite DNA region. We found no evidence to suggest that this split alpha-satellite DNA region has reduced or impaired the function of the centromere or that it contributed to the phenotype of the propositus. The FISH technique critically demonstrated the involvement of a whole-arm translocation in this case and provided accurate identification of breakpoints, which was not possible with standard banding techniques.

20 p duplication as a result of parental translocation

Grammatico P, Cupilari F, Di Rosa C, Falcolini M, Del Porto G
Clin Genet 1992 Jun;41(6):285-9 
We report two related patients, presenting duplication 20p, with a characteristic phenotype including normal growth pattern, mental and psychomotor retardation, reduced motor coordination, poor language development, round face and prominent cheeks, vertebral and dental anomalies, and renal malformations. Familial chromosome analysis showed a balanced translocation t(20;21)(p11;q22) in three members of the family. These cases, together with those previously reported in the literature, allow us to make a better delineation of the duplication 20p syndrome, identifying more clearly the symptoms that must be considered as characteristic of this clinical picture.

Partial trisomy 20p resulting from a recombination of a familial pericentric inversion.

Hum Genet 1986 Dec;74(4):417-9 
Bown N, Cross I, Davison EV, Burn J
Recombination of an inherited pericentric inversion of chromosome 20 has given rise to a child with partial trisomy 20p. To our knowledge no previous familial inversions of this chromosome have been described in the literature.

Trisomy 20p: case report and genetic review.

J Genet Hum 1985 Jan;33(1):67-75 
Lurie IW, Rumyantseva NV, Zaletajev DV, Gurevich DB, Korotkova IA
Partial trisomy for the distal part of the short arm of chromosome 20 reported in a girl aged 11/2 years with typical craniofacial dysmorphies and psychomotor retardation. The trisomy resulted from a paternal translocation t(14;20) (q32.3;p11.1). The review of 25 cases of partial trisomy 20p showed that most cases (22 : 25) were due to parental translocations. Predominant involvement of small chromosomes in translocations with chromosome 20 was also detected.

Trisomy 20p derived from a maternal pericentric inversion and brachymesophalangy of the index finger

Ann Genet 1985;28(3):167-71 [Article in French] 
Lucas J, Le Mee F, Le Marec B, Pluquailec K, Journel H, Picard F
The article brings to light the very first case of trisomy 20p resulting from a maternal pericentric inversion in a 2 1/2-year old boy. The study outlines the characteristic clinical features of the syndrome, i.e. round face, upslanting palpebral fissures, microretrognathia, normal growth, slight psycho-motor retardation and congenital heart defects. The association of the der(20) inv(20) (p112q133) mat and brachymesophalangy of index ("Mohr-Wriedt" type of brachydactyly) enables the authors to suggest that chromosome 20 may be held responsible for this particular malformation.

"De Novo" trisomy 20p with macroorchidism in a prepuberal boy.

Ann Genet 1984;27(1):58-9 
Balestrazzi P, Virdis R, Frassi C, Negri V, Rigoli E, Bernasconi S
A 9-year-old prepuberal boy with trisomy 20p syndrome and previously undescribed macroorchidism is presented. This is the second report of trisomy 20p originated "de novo" supporting a frequency rate of about the 10% for this etiological mechanism. Reviewing the most common clinical findings of all 19 previous patients, a typical phenotype with a recognizable face can be carried out in several cases. If prepuberal macroorchidism is confirmed in further patients, trisomy 20p could be taken into account in the differential diagnosis with the sex-linked syndromes with mental retardation and abnormal testicular increase.

Trisomy 20p due to a paternal reciprocal translocation.

Ann Genet 1983;26(2):94-7
Funderburk SJ, Sparkes RS, Sparkes MC
A mentally retarded boy with multiple malformations was found to have trisomy for the distal two-thirds of the short arm of chromosome 20 (trisomy 20p), resulting from a paternal translocation (5;20)(p15;p11). The patient had a cleft palate, a feature not present in other trisomy 20p patients. A review of the reported trisomy 20p patients indicates that their varied features do no constitute a readily recognizable clinical syndrome.

Trisomy 20p from maternal t(3;20) translocation.

J Med Genet 1979 Jun;16(3):229-32 
Archidiacono N, Tecilazich D, Tonini G, Rocchi M, Filippi G
A case of trisomy 20p resulting from a maternal translocation t(3;20) is described. QM and BUdR banding techniques were used for its identification. A round face with oblique palpebral fissures, strabismus, cardiac and vertebral abnormalities, mild psychomotor retardation, together with poor coordination and speech impediment, are the most typical features of the proband.

Triplication of chromosome arm 20p due to inherited translocation and secondary nondisjunction.

Am J Med Genet 1979;4(1):47-50 
Marcus ES, Fuller B, Riccardi VM
A patient with triplication of all of chromosome arm 20p is presented to illustrate the relatively modest degree of developmental delay that can result from autosomal triplication and the role of nondisjunction as a mechanism for deriving a partial triplication status.

A cascade of chromosomal aberrations in three generations: a fragile 16q, an extra fragment and a rearranged 20.

Ann Genet 1978 Dec;21(4):209-14 
Cote GB, Papadakou-Lagoyanni S, Pantelakis S
The propositus' grandmother has a fragile 16q and belongs to a large family where several abortions and congenital anomalies were recorded. The portion distal to the fragile site was inherited as an extra fragment by the proposius' father who has it in 11% of his lymphocyte metaphases. This phenotypically harmless fragment has a high affinity for satellited chromosomes and was probably a main factor in the causation of the rearrangement that produced the partial trisomy 20p found in the propositus.

Familial trisomy 20p five cases and two carriers in three generations

Ann Genet 1977 Jun;20(2):77-83 
Centerwall W, Francke U
A clinically normal mother of three retarded children has been determined by G-banding to have a balanced translocation 46,XX,t(13;20) (q34;p11.2). The children each have an unbalanced form of the translocation with partial trisomy for 20p. Extensive gene marker studies have been unable to affix any specific gene locus onto the short arm of chromosome 20. The balanced translocation was inherited from the maternal grandfather. Two phenotypically abnormal deceased members of the family are believed to have had the unbalanced trisomy 20p condition. An increases number of spontaneous abortions were possibly due to lethal unbalanced 20p deletions. The moderate to mild mental retardation and somewhate unusual features (round face, prominent cheeks and nose, short mandible) in the three siblings and two other affected relatives suggest that trisomy of the short arm of chromosome 20 may cause a distinguishable clinical syndrome. Vertebral abnormalities and abnormal dermatoglyphics are part of the picture. Clinical and cytogenetic findings of all reported cases are compared.

Partial trisomy 20p derived from a t(18;20) translocation.

Hum Genet 1976 Oct 28;34(2):155-62 
Taylor KM, Wolfinger HL, Brown MG, Chadwick DL, Francke U
Two sibs show a strikingly concordant syndrome of congenital anomalies and G-banding reveals that each has partial trisomy 20p resulting from a t(18;20) translocation. They resemble other cases of partial trisomy 20p in some respects but also differ in some ways. Their normal sib, mother, and half-aunt are balanced heterozygotes for the t(18;20) translocation. The segregation of the balanced translocation in this family is associated with an extremely poor reproductive record. The segregation pattern closely parallels that of a t(13;20) translocation in a family described by Carrel et al. (1971) and Francke (1972). The similarity of segregation patterns is predictable on the basis of probable pachytene configurations, but the dissimilarity of phenotypes between families is not readily explained.

Supernumerary ring chromosome 20 characterized by fluorescence in situ hybridization.

Clin Genet 1996 Jan;49(1):49-53 
van Langen IM, Otter MA, Aronson DC, Overweg-Plandsoen WC, Hennekam RC, Leschot NJ, Hoovers JM
We report on a boy with mild dysmorphic features and developmental delay, in whom karyotyping showed an additional minute ring chromosome in 60% of metaphases. Fluorescence in situ hybridization (FISH) with a centromere specific probe demonstrated that the ring chromosome contained the centromeric region of chromosome 20. The ring was highlighted completely using a chromosome 20 painting probe. A cosmid probe for 20p 12-13 gave a positive signal and hybridization with an all-telomere probe showed no signal, suggesting a breakpoint in the 20p telomere. The results suggested that only a small part of 20q was involved in this ring. The ring was also detected in 18% of nuclei of a buccal smear. The phenotypic similarities of symptoms in the proband to patients with a (partial) trisomy 20p and the dissimilarities to symptoms in patients with (partial) trisomy 20q were in agreement with the FISH results.

[Medline has 170 studies containing 'delet* And chromosome 20' of which 31 have 20p]

Deleted chromosome 20 from a patient with Alagille syndrome isolated in a cell hybrid through leucine transport selection: study of three candidate genes.

Mamm Genome 1994 Nov;5(11):663-9 
Deleuze JF, Dhorne S,.. Deschatrette J, Alagille D, Hadchouel M
Alagille syndrome (AGS) is a well-defined genetic entity assigned to the short arm of Chromosome (Chr) 20 by a series of observations of AGS patients associated with microdeletions in this region. By fusing lymphoblastoid cells of an AGS patient that exhibited a microdeletion in the short arm of Chr 20 encompassing bands p11.23 to p12.3 with rodent thermosensitive mutant cells (CHOtsH1-1) deficient in-leucyl-tRNA synthetase, we isolated a somatic cell hybrid segregating the deleted human Chr 20.

This hybrid clone, designated NR2, was characterized by several methods, including PCR, with eight pairs of oligonucleotides mapped to Chr 20: D20S5, D20S41, D20S42, D20S56, D20S57, D20S58, adenosine deaminase (ADA), and Prion protein; RFLP) analyses with four genomic anonymous probes (D20S5, cD3H12, D20S17, D20S18); and fluorescent in situ hybridization (FISH) with total human DNA and D20Z1, a sequence specific to the human Chr 20 centromere, as probes. The NR2 hybrid allowed us to exclude three candidate genes for AGS: hepatic nuclear factor 3 beta (HNF3 beta), paired box 1 (PAX1), and cystatin C (CST3) as shown by their localization outside of the deletion. The NR2 hybrid is a powerful tool for the mapping of new probes of this region, as well as for obtaining new informative probes specific for the deletion by subtractive cloning of the region. Such markers will be useful for linkage analysis and screening of cDNA libraries.

Acta Paediatr Jpn 1997 Dec;39(6):647-52 later notes, "Alagille syndrome (AGS) is a genetic disease and the responsible gene has already been mapped at 20p12. To more accurately detect the region of the AGS gene on the linkage map of chromosome 20p, 14 yeast artificial chromosome (YAC) clones were screened to construct a YAC contig in the candidate region and 13 locus markers and 2 sequence-tagged sites (STS) were ordered. Combining all of the analyses, a 1.3 Mb critical region from D20S507 to D20S61 for the AGS gene was identified. As the human Jagged 1 gene (JAG1) lies just in this region and is responsible for the AGS disease.... See also Genomics 1997 Aug 1;43(3):376-9 and Nat Genet 1997 Jul;16(3):235-42.

Partial trisomy 10p in combination with partial monosomy 20p--a syndrome with muscular hypotonia, psychomotor retardation, dwarfism and craniofacial dysmorphia

Klin Padiatr 1990 Sep-Oct;202(5):352-4 [Article in German] 
Meyer R
The clinical syndrome resulting from deletion of 20p in combination with duplication of 10p, seen in two male members of the same family, is reported for the first time. The sister of one and the mother of the other patient are asymptomatic carriers of a balanced translocation. The two patients have multiple stigmata including dwarfism and pronounced psychomotoric retardation. The syndrome corresponds largely to an addition of the symptoms seen in cases with deletion of 20p and duplication of 10p reported hitherto.

Autism and maternally derived aberrations of chromosome 15q.

Am J Med Genet 1998 Apr 1;76(4):327-36 
Schroer RJ, Phelan MC, Michaelis RC, ... Stevenson RE
Of the chronic mental disabilities of childhood, autism is causally least well understood. The former view that autism was rooted in exposure to humorless and perfectionistic parenting has given way to the notion that genetic influences are dominant underlying factors. Still, identification of specific heritable factors has been slow with causes identified in only a few cases in unselected series. A broad search for genetic and environmental influences that cause or predispose to autism is the major thrust of the South Carolina Autism Project. Among the first 100 cases enrolled in the project, abnormalities of chromosome 15 have emerged as the single most common cause. The four abnormalities identified include deletions and duplications of proximal 15q. Other chromosome aberrations seen in single cases include a balanced 13;16 translocation, a pericentric inversion 12, a deletion of 20p, and a ring 7.

Monosomy 20 in childhood acute lymphoblastic leukemia.

Silengo M, Vassallo E, Barisone E, Miniero R, Madon E
Cancer Genet Cytogenet 1992 Apr;59(2):177-9 
We report two cases of acute lymphoblastic leukemia (ALL) with loss of chromosome 20 as the only karyotypic abnormality detected in the blast cells. The first patient is a 12-year-old boy studied at diagnosis. He represents the only case of monosomy 20 in our series of 90 pediatric ALL successfully karyotyped at diagnosis. In the second patient, monosomy 20 was detected at the second hematologic relapse, 12 years after the initial diagnosis; cytogenetic studies were not performed at disease onset.

Monosomy 20: a nonrandom finding in childhood acute lymphoblastic leukemia.

Betts DR, Kingston JE, Dorey EL, Young BD, Webb D, Katz FE, Gibbons B
Genes Chromosomes Cancer 1990 Sep;2(3):182-5 
We describe four cases of childhood acute lymphoblastic leukemia with monosomy 20 as the sole cytogenetic abnormality. These cases represent 3.4% of cytogenetically abnormal childhood ALL studied in our institute at diagnosis. The patients presented at similar age, ranging from 31 to 36 months. All four patients remain in first remission with survival time being at least 20 months from the time of diagnosis.

Low frequency of monosomy 20 mosaicism in a liveborn infant with minor dysmorphic features.

Lancet 1991 Mar 30;337(8744):803-4 
Wallerstein DF, Wallerstein R, Watkins C

Thirteen genes (Cebpb, E2f1, Tcf4, Cyp24, Pck1, Acra4, Edn3, Kcnb1, Mc3r, Ntsr, Cd40, Plcg1 and Rcad) that probably lie in the distal imprinting region of mouse chromosome 2 are not monoallelically expressed.

Genet Res 1995 Apr;65(2):83-93 
Williamson CM, Dutton ER, Abbott CM, Beechey CV, Ball ST, Peters J
Seven imprinted genes are currently known in the mouse but none have been identified yet in the distal imprinting region of mouse Chromosome (Chr) 2, a region which shows striking linkage conservation with human chromosome 20q13. Both maternal duplication/paternal deficiency and its reciprocal for distal Chr 2 lead to mice with abnormal body shapes and behavioural abnormalities. We have tested a number of candidate genes, that are either likely or known to lie within the distal imprinting region, for monoallelic expression. These included 3 genes (Cebpb, E2f1 and Tcf4) that express transcription factors, 2 genes (Cyp24 and Pck1) that are involved in growth, 5 genes (Acra4, Edn3, Kcnb1, Mc3r and Ntsr) where a defect could lead to neurological and probably behavioural problems, and 3 genes (Cd40, Plcg1 and Rcad) that are less obvious candidates but sequence information was available for designing primers to test their expression.... None of the 13 genes is monoallelically expressed in the appropriate tissues before and shortly after birth which suggests that these genes are not imprinted later in development...Since there is considerable evidence of conservation of imprinting between mouse and human, we would predict that the 13 genes are not imprinted in human. Five of the genes: E2f1, Tcf4, Kcnb1, Cd40 and Rcad, have not yet been mapped in human. However, because of the striking linkage conservation observed between mouse Chr 2 and human chromosome 20, we would expect these genes to map on human chromosome 20q13.

Parental origin of transcription from the human GNAS1 gene.

J Med Genet 1994 Aug;31(8):607-14 
Campbell R, Gosden CM, Bonthron DT
Variation in the phenotypic expression of Albright's hereditary osteodystrophy (AHO) determined by the parent of transmission, suggests that the human Gs alpha gene (GNAS1), in which mutations occur in AHO, may be under imprinted control. GNAS1 is also known to map to a chromosomal region (20q13.11) showing syntenic homology with the imprinted mouse region 2E1-2H3. ... If genomic imprinting regulates the expression of the human GNAS1 gene, our data suggest that the effect must either be subtle and quantitative, or be confined to a small subset of specialised hormone responsive cells within the target tissues.

...A cDNA encoding the human GABAA receptor beta 3 subunit has been isolated from a brain cDNA library and its nucleotide sequence has been determined. This gene, GABRB3, has recently been mapped to human chromosome 15q11q13, the region deleted in Angelman and Prader-Willi syndromes. The association of distinct phenotypes with maternal versus paternal deletions of this region suggests that one or more genes in this region show parental-origin-dependent expression (genetic imprinting).

.-- Hypocalcemia and hyperphosphatemia caused by parathyroid hormone (PTH)-resistance are the only discernible abnormalities in pseudohypoparathyroidism type Ib (PHP-Ib). Because mutations in the PTH/PTH-related peptide receptor, a plausible candidate gene, had been excluded previously, we conducted a genome-wide search with four PHP-Ib kindreds and established linkage to a small telomeric region on chromosome 20q, which contains the stimulatory G protein gene. We, furthermore, showed that the genetic defect is imprinted paternally and thus is inherited in the same mode as the PTH-resistant hypocalcemia in kindreds with PHP-Ia and/or pseudo-pseudohypoparathyroidism, two related disorders caused by different stimulatory G protein mutations. PNAS 1998 Sep 29;95(20):11798-803

PNAS Vol. 95, Issue 26, 15475-15480, December 22, 1998

"Although GNAS1 therefore is clearly imprinted, the maternal inheritance of PHP-Ia still suggests that there may be a gene product that is exclusively maternally rather than paternally derived. After a search aimed at identifying additional GNAS1 transcripts that may be imprinted, we now report the presence of an additional promoter and first exon, located 11›kb upstream of the XLs exon. Remarkably, and in complete contrast to the XLs exon, this region is paternally methylated, and the promoter is active only on a maternal allele. The new exon includes the entire coding region of the human homologue of the bovine neuroendocrine secretory granule protein NESP55 (17). Like the XLs exon, the NESP55 exon is spliced onto GNAS1 exons 2-13. GNAS1 is thus a gene of bizarre complexity from the point of view of its imprinting. It encodes distinct paternally (XLs), maternally (NESP55), and biallelically (Gs) expressed proteins. The paternally and maternally active promoters are separated by only 11›kb. Furthermore, the two structurally unrelated paternal and maternal protein products, XLs and NESP55, both appear to be involved specifically in the formation of secretory granules in neuroendocrine cells.

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