Login to MyKarger

New to MyKarger? Click here to sign up.



Login with Facebook

Forgot your password?

Authors, Editors, Reviewers

For Manuscript Submission, Check or Review Login please go to Submission Websites List.

Submission Websites List

Institutional Login
(Shibboleth or Open Athens)

For the academic login, please select your country in the dropdown list. You will be redirected to verify your credentials.

Review

Free Access

Role of Phosphoinositide-Specific Phospholipase C η2 in Isolated and Syndromic Mental Retardation

Lo Vasco V.R.

Author affiliations

Department of Organi di Senso, University of Rome ‘Sapienza’, Rome, Italy

Corresponding Author

Vincenza Rita Lo Vasco, MD, PhD

Department of Organi di Senso, University of Rome ‘Sapienza’

Viale del Policlinico, 155

IT–00185 Rome (Italy)

Tel. +39 064 997 6814, E-Mail ritalovasco@hotmail.it

Related Articles for ""

Eur Neurol 2011;65:264–269

Abstract

Deletions in the distal region of the short arm of chromosome 1 (1p36) are widely diffuse, both as somatic abnormalities in tumors and as constitutive in the congenital 1p36 deletion syndrome. The deletion size varies from 1.5 to 10 Mb, with common breakpoints located from 1p36.13 to 1p36.33. Patients bearing constitutional deletion of a smaller region, 1p36.3, present with a number of features, including mental retardation. The gene PLCH2, codifying for the phosphoinositide-specific phospholipase C (PI-PLC) η2, maps on the 1p36.32 region. PI-PLC η2, expressed in the brain after birth, is a key enzyme in cellular calcium mobilization. In the brain, calcium plays a role in axon growth and retraction, growth cone guidance, synapse formation, and responses to various neurotransmitters. For its role in the nervous system, PI-PLC η2 might be a putative candidate gene for the neurodevelopmental delay observed in patients bearing 1p36.3 deletions.

© 2011 S. Karger AG, Basel


Introduction

Mental retardation (MR) affects 2–3% of the population, but its causes remain unexplained in 40% of the cases. Subtle telomeric rearrangements are responsible for about 1% of MR [1]. Deletions in the distal region of the short arm of chromosome 1 (1p36) are widely diffuse, both as somatic abnormalities in tumors [2] and as congenital syndrome. Constitutional deletion of 1p36 results in a recognizable syndromic pattern (1p36 deletion syndrome, OMIM #607872) considered due to the deletion of contiguous genes. The syndrome is characterized by a number of features, including MR of variable degree [3,4]. The frequency of monosomy 1p36 is 1 in 5–10,000 births [4,5]. Deletions occur equally in both females and males and no ethnicity differences have been registered [4,5].

The first constitutional deletion of chromosome 1p36 was described in a child presenting with neuroblastoma (NB) [6]. Besides MR, features were reported, including a typical dysmorphism characterized by microcephaly, brachycephaly, prominent forehead, midface hypoplasia, pointed chin, deep-set eyes, flat nasal bridge, and low set or asymmetric ears with thickened helices; facial clefting was also described [7,8]. Features also include vision and hearing problems, seizures and growth delay [9]. Occasionally, hypothyroidism and heart defects were described [4]. Patients with redundant skin on the nape and neck [10], intestinal malrotation and annular pancreas [11], spinal stenosis [12], skin teleangiectasies and hyperpigmentation associated to polydactyly [13], and gastrointestinal problems [4] were also described.

Prenatal features of 1p36 deletion syndrome were described, including intrauterine growth retardation, and multiple congenital anomalies, especially of the brain, such as ventriculomegaly or hydrocephalus, cerebral atrophy, leukoencephalopathy, and abnormalities or agenesis of the corpus callosum [14]. Polymicrogyria, periventricular nodular heterotopia, and pachygyria were also described [15].

Deletions involving a smaller region, 1p36.3, were identified in 0.5–0.7% of isolated MR [16], suggesting that this might represent the critical region containing one or more genes contributing to the neurological manifestations.

Cytogenetics and Clinical Data

Deletion of the 1p36 region results from both interstitial and terminal deletions of variable size and different breakpoints, as characterized by overlapping BAC contigs spanning 10.5 Mb [17]. About 95% of the deletions arise de novo, 60% occurring on the maternally and 40% on the paternally derived chromosome [17]. Deletions vary from size 1.5 to 10 Mb, with common breakpoints located from 1p36.13 to 1p36.33 [18]. The great number of genes mapping in this region complicates the identification of candidate genes involved in specific features. Moreover, it was observed that the severity of the phenotype is only partially related to the extent of the deletion.

A premeiotic model for the generation of complex rearrangements in the 1p36 region, such as successive progression of breakage, fusion and bridging events, has been proposed [19]. As some of the identified breakpoints fall within repetitive DNA, these sequences might play a role in 1p36 deletions [4]. Therefore, segmental duplications, low copy repeats and short repetitive DNA sequence elements might mediate the generation and/or the stabilization of 1p36 terminal deletions [19]. Non-allelic recombination of homologous palindromic low copy repeats at 1p36 terminal might also result in complex rearrangements [20]. Copy number variation also seems to influence gene expression by disrupting coding sequences, perturbing long-range gene regulation or altering gene dosage [21].

Four classes of rearrangements were suggested for terminal deletions of 1p36: simple terminal truncations, interstitial deletions, derivative chromosomes and more complex rearrangements involving other chromosome pairs [22]. The observed phenotypes might be the result of gene disruption, but it was suggested that deletion of dosage-sensitive genes and inversion, perhaps resulting in a position effect of adjacent chromatin, might also contribute [23,24,25].

However, the above mechanisms do not fully describe complex rearrangements. Authors agree that more complex models or simultaneous occurrence of multiple events cannot be excluded. The precise localization of the breakpoints in subjects with apparently pure deletion might help to speculate about the role of single genes on the clinical features, but the variability of the deletion sizes do not completely explain the phenotypic variability among patients. Some authors suggested that the phenotype associated to monosomy 1p36 might be due to a position effect rather than a contiguous gene syndrome. In fact, 2 patients exhibiting similar clinical findings but non-overlapping deletions were described [26].

MR, developmental delay and/or learning disabilities are present in nearly 100% of 1p36 deletion syndrome-affected patients [4]. No correlation between the severity of the neurological impairment and the deletion size has been identified. Attempts to correlate patients’ clinical features and outcome, deleted band size and candidate genes are still ongoing. A more precise refinement of the deletion breakpoint by using molecular cytogenetic techniques allowed the identification of smaller deleted regions.

An array comparative genomic hybridization on subjects affected with Smith-Magenis-like phenotype allowed the identification of a 44-year-old woman bearing the deletion of 1p36.32-33. The patient presented with short stature, obesity, prognathism, dental anomalies, brachydactyly, scoliosis, eye anomalies, chronic ear and respiratory infections, sleep and behavioral problems. The patient also presented with learning difficulties [27].

A group of patients ranging in age from 3 to 47 years, bearing 1p36.3 monosomy, presented with microcephaly, prominent forehead, deep set eyes, flat nasal bridge, midface hypoplasia, relative prognathism, brain anomalies, optic atrophy, ear anomalies, hearing loss and skeletal deformities [12]. These patients also had MR [12].

A female patient bearing a de novo deletion of 1p36.32-33 partially presenting with Prader-Willy syndrome features showed mild MR and behavioral problems [28].

A female infant bearing a de novo unbalanced 1;18 translocation causing 1p36-pter monosomy presented with facial dysmorphism, virilization of the external genitalia and psychomotor retardation [29].

A 14-year-old male patient bearing a complex rearrangement of 1p36.3, including interstitial deletion of about 1 Mb at the 1p36.32 region, presented with congenital bilateral cataract, blepharophimosis, ptosis, choanal atresia, deafness, short neck, skeletal anomalies, transient hypogammaglobulinemia, growth delay and MR with seizures and speech absence [30].

A female patient bearing 1p36.3 deletion presented with dysmorphism, NB and MR [31].

Although data remain controversial, MR seems to be constantly present in patients bearing 1p36.3 rearrangements. As a matter of fact, deletions of 1p36.3 are associated to neurodevelopmental impairment of variable degree, suggesting that this region might contain one or more genes associated with neurological features.

Notwithstanding the great number of cases, the complexity of the karyotypes, the variable size of pure deletions and the presence of numerous genes in the region of interest do not help to clarify the relationship with the clinical features. No candidate genes have been identified, although attempts have been made in order to obtain a genotype-phenotype correlation.

The proto-oncogene V-Ski Avian Sarcoma Viral Oncogene Homolog (SKI; OMIM *164780) is considered a likely candidate for the cleft lip/palate found in 17% of monosomy 1p36.3 patients [32].

A gene regulating the closure of craniofacial sutures (matrix metalloprotease 23 A, MMP23A; OMIM *603320; matrix metalloprotease 23 B; OMIM *603321) was mapped on chromosome 1p36.3 [33].

The potassium channel, voltage-gated, shaker-related subfamily, beta member 2 gene (KCNAB2; OMIM *601142) was deleted in the majority of seizures presenting patients with 1p36.3 deletion [34].

The human γ-aminobutyric acid A receptor δ-subunit gene (GABRD; OMIM *137163), located at 1p36.3, was suggested to be implicated in abnormal neurodevelopment [35]. By contrast, the finding of a patient bearing a complex rearrangement including 1p36.32 deletion in which GABRD locus was not involved suggested that the neurological features might be correlated to the anomalous expression of other genes [36]. The patient, a 9-year-old female, presented with dysmorphic features including a small mouth with heaped-up palate, small chin and small overfolded ears, straight eyebrows, fifth finger clinodactyly and short toes. A slightly similar dysmorphism was described in the mother and in 2 sisters, whose cytogenetic analyses did not highlight anomalies. The patient had learning disability, ear problems and hypermetropia. Prenatal scan had detected nuchal edema and ventriculomegaly. Developmental retardation such as delayed ability to sit, speech delay, and late walking at 22 months was also reported. Molecular cytogenetic analyses in the proband detected 1p36.32 deletion between 1.4 and 2 Mb long not involving the GABRD locus [36]. The authors suggested the existence of association among learning difficulties, developmental delay and 1p36.32 deletion. Further analyses detected deletion of the phosphoinositide (PI)-specific phospholipase C (PI-PLC) η2 codifying gene (PLCH2; OMIM *612836), which maps on 1p36.32 [36] (fig. 1).

Fig. 1

Chromosome 1 (human pair) showing the position of PLCH2, in the 1p36.32 region, and the flanking markers D1S243 and D1S468.

http://www.karger.com/WebMaterial/ShowPic/219910

Discussion

PI-PLC η2 belongs to the PI-PLC family, enzymes triggering the activation of protein kinase C and the release of calcium ions [37]. PI-PLCs play a central role in PI metabolism by regulating their spatiotemporal balance [37]. As a response to different stimuli, the binding of a signaling molecule to a G-protein-linked receptor in the plasma membrane (Gq) activates PI-PLC. In less than a second, PI-PLC cleaves the polar head group of phosphatydil-inositol bisphosphate (PIP2) into diacylglycerol (DAG) and inositol trisphosphate (IP3), both crucial molecules in signal transduction. DAG is an activator of several types of effector proteins. IP3 induces calcium release from the endoplasmic reticulum. The initial calcium increase induced by IP3 propagates as a wave through the cytoplasm often followed by a series of spikes. Being a pleiotropic messenger, calcium is a crucial mediator in many cell and tissue activities, including modifications of gene expression triggered through changes of its concentration. In instance, various studies showed that increase in cytoplasmic calcium is required for progression through the cell cycle, for actin polymerization and subsequent cell migration [37].

PI-PLC isoforms are codified by different genes. Each isoform has more than one alternative splicing variant, probably having slightly different activity [37].

Thirteen mammalian PI-PLC isoforms have been identified, divided into six sub-families on the basis of amino acid sequence, domain structure and mechanism of recruitment in response to activation [37]. Isoforms within the sub-families share the greatest sequence similarity and common domain organization, also sharing a general regulatory mechanism specific to the family [37].

The most recently identified sub-family is PI-PLC η, existing in two isoforms, η1 and η2. Expression of PI-PLC η2 is restricted to the central nervous system, occurs after birth and continues throughout the adult life. PI-PLC η2 is expressed in primary cultured neurons but not in astrocytes [38]. PI-PLC η2 is a key player in calcium mobilization and signaling in neurons [39]. In the brain, calcium is involved in complex events such as axon growth and retraction, growth cone guidance, synapse formation, and response to neurotransmitters [40].

In vivo, PI-PLC η2 is abundantly expressed in hippocampal pyramidal cells and olfactory bulb [40], organs which contribute to memory circuits. PI-PLC η2 is also expressed in the cerebral cortex, a region involved in memory, thinking and understanding language processes [40]. These data suggest that PI-PLC η2 might be involved in these functions. PI-PLC η2 was also found abundant in mouse habenula and retina, which both contribute to regulate the circadian rhythm [41].

The gene PLCH2, which codifies for PI-PLC η2 enzyme, maps on the 1p36.32 region. Remarkably, involvement of no other candidate gene located in the same region was confirmed to be associated to the MR/brain abnormalities described in the 1p36 deletion syndrome. In fact, molecular cytogenetic analysis performed in 1 patient presenting with MR and learning disability detected the presence of GABRD loci. These data suggested to exclude the involvement of GABRD in the neurological manifestations [36]. Moreover, the 1p36.32 region was found deleted in a small percentage of isolated MR [16], in a number of patients presenting with mild MR and/or behavioral problems and/or learning disability [12,24,25,26,27,28] and in a patient presenting with MR and altered regulation of the circadian rhythm such as sleeping disorders [26]. These observations suggest that PLCH2 might be a putative candidate gene for the brain/mental alterations due to its role in the central nervous system. In fact, 1p36.32 deletion causes the absence of PI-PLC η2 enzyme following the deletion of PLCH2 gene.

As PI-PLC η2 is involved in the formation and maintenance of neuronal networks and memory circuits, its absence might imply impairment of these functions and subsequent abnormal neuronal and intellectual development.

Further studies are required to verify this hypothesis, experimentally analyzing the function of PI-PLC η2 and verifying the presence of PLCH2 anomalies such as deletions/mutations in patients presenting with MR, both syndromic and isolated.

Acknowledgments

The author thanks Mario De Meo and Patrizia Simonetti for technical assistance.

Disclosure Statement

The author has no conflicts of interest to declare.


References

  1. Knight SJ, Horsley SW, Regan R, Lawrie NM, Maher EJ, Cardy DL, Flint J, Kearney L: Development and clinical application of an innovative fluorescence in situ hybridization technique which detects submicroscopic rearrangements involving telomeres. Eur J Hum Genet 1997;5:1–8.
  2. Lo Vasco VR: 1p36.32 rearrangements and the role of PI-PLC η2 in nervous tumours. J Neurooncol 2010, Epub ahead of print.
  3. Slavotinek A, Rosenberg M, Knight S, Gaunt L, Fergusson W, Killoran C, Clayton-Smith J, Kingston H, Campbell RH, Flint J, Donnai D, Biesecker L: Screening for submicroscopic chromosome rearrangements in children with idiopathic mental retardation using microsatellite markers for the chromosome telomeres. J Med Genet 1999;36:405–411.
  4. Gajecka M, Mackay KL, Shaffer LG: Monosomy 1p36 deletion syndrome. Am J Med Genet C Semin Med Genet 2007;145:346–356.
  5. Shapira SK, McCaskill C, Northrup H, Spikes AS, Elder FF, Sutton VR, Korenberg JR, Greenberg F, Shaffer LG: Chromosome 1p36 deletions: the clinical phenotype and molecular characterization of a common newly delineated syndrome. Am J Hum Genet 1997;61:642–650.
  6. Biegel JA, White PS, Marshall HN, Fujimori M, Zackai EH, Scher CD, Brodeur GM, Emanuel BS: Constitutional 1p36 deletion in a child with neuroblastoma. Am J Hum Genet 1993;52:176–182.
  7. Battaglia A: Del 1p36 syndrome: a newly emerging clinical entity. Brain Dev 2005;27:358–361.
  8. Battaglia A, Hoyme HE, Dallapiccola B, Zackai E, Hudgins L, McDonald-McGinn D, Bahi-Buisson N, Romano C, Williams CA, Braley LL, Zuberi SM, Carey JC: Further delineation of deletion 1p36 syndrome in 60 patients: a recognizable phenotype and common cause of developmental delay and mental retardation. Pediatrics 2008;121:404–410.
  9. Bahi-Buisson N, Guttierrez-Delicado E, Soufflet C, Rio M, Cormier Daire V, Lacombe D, Heron D, Verloes A, Zuberi S, Burglen L, Afenjar A, Moutard ML, Edery P, Novelli A, Bernardini L, Dulac O, Nabbout R, Plouin P, Battaglia A: Spectrum of epilepsy in terminal 1p36 deletion syndrome. Epilepsia 2008;49:509–515.
  10. Wang BT, Chen M: Redundant skin over the nape in a girl with monosomy 1p36 caused by a de-novo satellited derivative chromosome: a possible new feature? Clin Dysmorphol 2004;13:107–109.
  11. Minami K, Boshi H, Minami T, Tamura A, Yanagawa T, Uemura S, Takifuji K, Kurosawa K, Tsukino R, Izumi G, Yoshikawa N: 1p36 deletion syndrome with intestinal malrotation and annular pancreas. Eur J Pediatr 2005;164:193–194.
  12. Reish O, Berry SA, Hirsch B: Partial monosomy of chromosome 1p36.3: characterization of the critical region and delineation of a syndrome. Am J Med Genet 1995;59:467–475.
  13. Keppler-Noreuil KM, Carroll AJ, Finley WH, Rutledge SL: Chromosome 1p terminal deletion: report of new findings and confirmation of two characteristic phenotypes. J Med Genet 1995;32:619–622.
  14. Faivre L, Morichon-Delvallez N, Viot G, Martinovic J, Pinson MP, Aubry JP, Raclin V, Edery P, Dumez Y, Munnich A, Vekemans M: Prenatal detection of a 1p36 deletion in a fetus with multiple malformations and a review of the literature. Prenat Diagn 1999;19:49–53.
  15. Neal J, Apse K, Sahin M, Walsh CA, Sheen VL: Deletion of chromosome 1p36 is associated with periventricular nodular heterotopia. Am J Med Genet A 2006;140:1692–1695.
    External Resources
  16. Giraudeau F, Taine L, Biancalana V, Delobel B, Journel H, Missirian C, Lacombe D, Bonneau D, Parent P, Aubert D, Hauck Y, Croquette MF, Toutain A, Mattei MG, Loiseau HA, David A, Vergnaud G: Use of a set of highly polymorphic minisatellite probes for the identification of cryptic 1p36.3 deletions in a large collection of patients with idiopathic mental retardation. J Med Genet 2001;38:121–125.
  17. Heilstedt HA, Ballif BC, Howard LA, Kashork CD, Shaffer LG: Population data suggest that deletions of 1p36 are a relatively common chromosome abnormality. Clin Genet 2003;64:310–316.
  18. Wu YQ, Heilstedt HA, Bedell JA, May KM, Starkey DE, McPherson JD, Shapira SK, Shaffer LG: Molecular refinement of the 1p36 deletion syndrome reveals size diversity and a preponderance of maternally derived deletions. Hum Mol Genet 1999;8:313–321.
  19. Ballif BC, Yu W, Shaw CA, Kashork CD, Shaffer LG: Monosomy 1p36 breakpoint junctions suggest pre-meiotic breakage-fusion-bridge cycles are involved in generating terminal deletions. Hum Mol Genet 2003;12:2153–2165.
  20. Chen Z, Grebe TA, Guan XY, Notohamiprodjo M, Nutting PJ, Stone JF, Trent JM, Sandberg AA: Maternal balanced translocation leading to partial duplication of 4q and partial deletion of 1p in a son: cytogenetic and FISH studies using band-specific painting probes generated by chromosome microdissection. Am J Med Genet 1997;71:160–166.
  21. Shaffer LG, Heilstedt HA: Terminal deletion of 1p36. Lancet 2001;358:S9.
  22. Ballif BC, Kashork CD, Shaffer LG: FISHing for mechanisms of cytogenetically defined terminal deletions using chromosome-specific subtelomeric probes. Eur J Hum Genet 2000;8:764–770.
  23. Gajecka M, Pavlicek A, Glotzbach CD, Ballif BC, Jarmuz M, Jurka J, Shaffer LG: Identification of sequence motifs at the breakpoint junctions in three t(1;9)(p36.3;q34) and delineation of mechanisms involved in generating balanced translocations. Hum Genet 2006;120:519–526.
  24. Gajecka M, Glotzbach CD, Shaffer LG: Characterization of a complex rearrangement with interstitial deletions and inversion on human chromosome 1. Chromosome Res 2006;14:277–282.
  25. Redon R, Rio M, Gregory SG, Cooper RA, Fiegler H, Sanlaville D, Banerjee R, Scott C, Carr P, Langford C, Cormier-Daire V, Munnich A, Carter NP, Colleaux L: Tiling path resolution mapping of constitutional 1p36 deletions by array-CGH: contiguous gene deletion or ‘deletion with positional effect’ syndrome? J Med Genet 2005;42:166–171.
  26. Kurosawa K, Kawame H, Okamoto N, Ochiai Y, Akatsuka A, Kobayashi M, Shimohira M, Mizuno S, Wada K, Fukushima Y, Kawawaki H, Yamamoto T, Masuno M, Imaizumi K, Kuroki Y: Epilepsy and neurological findings in 11 individuals with 1p36 deletion syndrome. Brain Dev 2005;27:378–382.
  27. Williams SR, Girirajan S, Tegay D, Nowak N, Hatchwell E, Elsea SH: Array comparative genomic hybridisation of 52 subjects with a Smith-Magenis-like phenotype: identification of dosage-sensitive loci also associated with schizophrenia, autism, and developmental delay. J Med Genet 2010;47:223–229.
  28. D’Angelo CS, Da Paz JA, Kim CA, Bertola DR, Castro CI, Varela MC, Koiffmann CP: Prader-Willi-like phenotype: investigation of 1p36 deletion in 41 patients with delayed psychomotor development, hypotonia, obesity and/or hyperphagia, learning disabilities and behavioral problems. Eur J Med Genet 2006;49:451–460.
  29. De Pater JM, Poot M, Beemer FA, Bijlsma JB, Hack WW, Van Dam WM, Eleveld MJ, Loneus WH, Engelen JJ: Virilization of the external genitalia and severe mental retardation in a girl with an unbalanced translocation 1;18. Eur J Med Genet 2006;49:19–27.
  30. Chen E, Obolensky E, Rauen KA, Shaffer LG, Li X: Cytogenetic and array CGH characterization of de novo 1p36 duplications and deletion in a patient with congenital cataracts, hearing loss, choanal atresia, and mental retardation. Am J Med Genet A 2008;146A: 2785–2790.
  31. Isidor B, Le Cunff M, Boceno M, Boisseau P, Thomas C, Rival JM, David A, Le Caignec C: Complex constitutional subtelomeric 1p36.3 deletion/duplication in a mentally retarded child with neonatal neuroblastoma. Eur J Med Genet 2008;51:679–684.
  32. Lu W, Volcik K, Zhu H, Wen S, Shaw GM, Lammer EJ, Finnell RH: Genetic variation in the proto-oncogene SKI and risk for orofacial clefting. Mol Genet Metab 2005;86:412–416.
  33. Gajecka M, Yu W, Ballif BC, Glotzbach CD, Bailey KA, Shaw CA, Kashork CD, Heilstedt HA, Ansel DA, Theisen A, Rice R, Rice DP, Shaffer LG: Delineation of mechanisms and regions of dosage imbalance in complex rearrangements of 1p36 leads to a putative gene for regulation of cranial suture closure. Eur J Hum Genet 2005;13:139–149.
  34. Schultz D, Litt M, Smith L, Thayer M, McCormack K: Localization of two potassium channel β-subunit genes, KCNA1B and KCNA2B. Genomics 1996;31:389–391.
  35. Emberger W, Windpassinger C, Petek E, et al: Assignment of the human GABAA receptor δ-subunit gene (GABRD) to chromosome band 1p36.3 distal to marker NIB1364 by radiation hybrid mapping. Cytogenet Cell Genet 2000;89:281–282.
  36. Fitzgibbon GJ, Clayton-Smith J, Banka S, Hamilton SJ, Needham MM, Dore JK, Miller JT, Pawson GD, Gaunt L: Array comparative genomic hybridisation-based identification of two imbalances of chromosome 1p in a 9-year-old girl with a monosomy 1p36-related phenotype and a family history of learning difficulties: a case report. J Med Case Reports 2008;2:355.
  37. Suh PG, Park J, Manzoli L, Cocco L, Peak JC, Katan M, Fukami K, Kataoka T, Yuk S, Ryu SH: Multiple roles of phosphoinositide-specific phospholipase C isozymes. BMB Rep 2008;41:415–434.
  38. Cockcroft S: The latest phospholipase C, PLCη, is implicated in neuronal function. Trends Biochem Sci 2006;31:4–7.
  39. Stewart AJ, Mukherjee J, Roberts SJ, Lester D, Farquharson C: Identification of a novel class of mammalian phosphoinositol-specific phospholipase C enzymes. Int J Mol Med 2005;15:117–121.
  40. Nakahara M, Shimozawa M, Nakamura Y, Irino Y, Morita M, Kudo Y, Fukami K: A novel phospholipase C, PLCη2, is a neuron-specific isozyme. J Biol Chem 2005;280:29128–29134.
  41. Kanemaru K, Nakahara M, Nakamura Y, Hashiguchi Y, Kouchi Z, Yamaguchi H, Oshima N, Kiyonari H, Fukami K: Phospholipase C-η2 is highly expressed in the habenula and retina. Gene Expr Patterns 2010;10:119–126.

Author Contacts

Vincenza Rita Lo Vasco, MD, PhD

Department of Organi di Senso, University of Rome ‘Sapienza’

Viale del Policlinico, 155

IT–00185 Rome (Italy)

Tel. +39 064 997 6814, E-Mail ritalovasco@hotmail.it


Article / Publication Details

First-Page Preview
Abstract of Review

Received: December 07, 2010
Accepted: March 08, 2011
Published online: April 08, 2011
Issue release date: May 2011

Number of Print Pages: 6
Number of Figures: 1
Number of Tables: 0

ISSN: 0014-3022 (Print)
eISSN: 1421-9913 (Online)

For additional information: https://www.karger.com/ENE


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Knight SJ, Horsley SW, Regan R, Lawrie NM, Maher EJ, Cardy DL, Flint J, Kearney L: Development and clinical application of an innovative fluorescence in situ hybridization technique which detects submicroscopic rearrangements involving telomeres. Eur J Hum Genet 1997;5:1–8.
  2. Lo Vasco VR: 1p36.32 rearrangements and the role of PI-PLC η2 in nervous tumours. J Neurooncol 2010, Epub ahead of print.
  3. Slavotinek A, Rosenberg M, Knight S, Gaunt L, Fergusson W, Killoran C, Clayton-Smith J, Kingston H, Campbell RH, Flint J, Donnai D, Biesecker L: Screening for submicroscopic chromosome rearrangements in children with idiopathic mental retardation using microsatellite markers for the chromosome telomeres. J Med Genet 1999;36:405–411.
  4. Gajecka M, Mackay KL, Shaffer LG: Monosomy 1p36 deletion syndrome. Am J Med Genet C Semin Med Genet 2007;145:346–356.
  5. Shapira SK, McCaskill C, Northrup H, Spikes AS, Elder FF, Sutton VR, Korenberg JR, Greenberg F, Shaffer LG: Chromosome 1p36 deletions: the clinical phenotype and molecular characterization of a common newly delineated syndrome. Am J Hum Genet 1997;61:642–650.
  6. Biegel JA, White PS, Marshall HN, Fujimori M, Zackai EH, Scher CD, Brodeur GM, Emanuel BS: Constitutional 1p36 deletion in a child with neuroblastoma. Am J Hum Genet 1993;52:176–182.
  7. Battaglia A: Del 1p36 syndrome: a newly emerging clinical entity. Brain Dev 2005;27:358–361.
  8. Battaglia A, Hoyme HE, Dallapiccola B, Zackai E, Hudgins L, McDonald-McGinn D, Bahi-Buisson N, Romano C, Williams CA, Braley LL, Zuberi SM, Carey JC: Further delineation of deletion 1p36 syndrome in 60 patients: a recognizable phenotype and common cause of developmental delay and mental retardation. Pediatrics 2008;121:404–410.
  9. Bahi-Buisson N, Guttierrez-Delicado E, Soufflet C, Rio M, Cormier Daire V, Lacombe D, Heron D, Verloes A, Zuberi S, Burglen L, Afenjar A, Moutard ML, Edery P, Novelli A, Bernardini L, Dulac O, Nabbout R, Plouin P, Battaglia A: Spectrum of epilepsy in terminal 1p36 deletion syndrome. Epilepsia 2008;49:509–515.
  10. Wang BT, Chen M: Redundant skin over the nape in a girl with monosomy 1p36 caused by a de-novo satellited derivative chromosome: a possible new feature? Clin Dysmorphol 2004;13:107–109.
  11. Minami K, Boshi H, Minami T, Tamura A, Yanagawa T, Uemura S, Takifuji K, Kurosawa K, Tsukino R, Izumi G, Yoshikawa N: 1p36 deletion syndrome with intestinal malrotation and annular pancreas. Eur J Pediatr 2005;164:193–194.
  12. Reish O, Berry SA, Hirsch B: Partial monosomy of chromosome 1p36.3: characterization of the critical region and delineation of a syndrome. Am J Med Genet 1995;59:467–475.
  13. Keppler-Noreuil KM, Carroll AJ, Finley WH, Rutledge SL: Chromosome 1p terminal deletion: report of new findings and confirmation of two characteristic phenotypes. J Med Genet 1995;32:619–622.
  14. Faivre L, Morichon-Delvallez N, Viot G, Martinovic J, Pinson MP, Aubry JP, Raclin V, Edery P, Dumez Y, Munnich A, Vekemans M: Prenatal detection of a 1p36 deletion in a fetus with multiple malformations and a review of the literature. Prenat Diagn 1999;19:49–53.
  15. Neal J, Apse K, Sahin M, Walsh CA, Sheen VL: Deletion of chromosome 1p36 is associated with periventricular nodular heterotopia. Am J Med Genet A 2006;140:1692–1695.
    External Resources
  16. Giraudeau F, Taine L, Biancalana V, Delobel B, Journel H, Missirian C, Lacombe D, Bonneau D, Parent P, Aubert D, Hauck Y, Croquette MF, Toutain A, Mattei MG, Loiseau HA, David A, Vergnaud G: Use of a set of highly polymorphic minisatellite probes for the identification of cryptic 1p36.3 deletions in a large collection of patients with idiopathic mental retardation. J Med Genet 2001;38:121–125.
  17. Heilstedt HA, Ballif BC, Howard LA, Kashork CD, Shaffer LG: Population data suggest that deletions of 1p36 are a relatively common chromosome abnormality. Clin Genet 2003;64:310–316.
  18. Wu YQ, Heilstedt HA, Bedell JA, May KM, Starkey DE, McPherson JD, Shapira SK, Shaffer LG: Molecular refinement of the 1p36 deletion syndrome reveals size diversity and a preponderance of maternally derived deletions. Hum Mol Genet 1999;8:313–321.
  19. Ballif BC, Yu W, Shaw CA, Kashork CD, Shaffer LG: Monosomy 1p36 breakpoint junctions suggest pre-meiotic breakage-fusion-bridge cycles are involved in generating terminal deletions. Hum Mol Genet 2003;12:2153–2165.
  20. Chen Z, Grebe TA, Guan XY, Notohamiprodjo M, Nutting PJ, Stone JF, Trent JM, Sandberg AA: Maternal balanced translocation leading to partial duplication of 4q and partial deletion of 1p in a son: cytogenetic and FISH studies using band-specific painting probes generated by chromosome microdissection. Am J Med Genet 1997;71:160–166.
  21. Shaffer LG, Heilstedt HA: Terminal deletion of 1p36. Lancet 2001;358:S9.
  22. Ballif BC, Kashork CD, Shaffer LG: FISHing for mechanisms of cytogenetically defined terminal deletions using chromosome-specific subtelomeric probes. Eur J Hum Genet 2000;8:764–770.
  23. Gajecka M, Pavlicek A, Glotzbach CD, Ballif BC, Jarmuz M, Jurka J, Shaffer LG: Identification of sequence motifs at the breakpoint junctions in three t(1;9)(p36.3;q34) and delineation of mechanisms involved in generating balanced translocations. Hum Genet 2006;120:519–526.
  24. Gajecka M, Glotzbach CD, Shaffer LG: Characterization of a complex rearrangement with interstitial deletions and inversion on human chromosome 1. Chromosome Res 2006;14:277–282.
  25. Redon R, Rio M, Gregory SG, Cooper RA, Fiegler H, Sanlaville D, Banerjee R, Scott C, Carr P, Langford C, Cormier-Daire V, Munnich A, Carter NP, Colleaux L: Tiling path resolution mapping of constitutional 1p36 deletions by array-CGH: contiguous gene deletion or ‘deletion with positional effect’ syndrome? J Med Genet 2005;42:166–171.
  26. Kurosawa K, Kawame H, Okamoto N, Ochiai Y, Akatsuka A, Kobayashi M, Shimohira M, Mizuno S, Wada K, Fukushima Y, Kawawaki H, Yamamoto T, Masuno M, Imaizumi K, Kuroki Y: Epilepsy and neurological findings in 11 individuals with 1p36 deletion syndrome. Brain Dev 2005;27:378–382.
  27. Williams SR, Girirajan S, Tegay D, Nowak N, Hatchwell E, Elsea SH: Array comparative genomic hybridisation of 52 subjects with a Smith-Magenis-like phenotype: identification of dosage-sensitive loci also associated with schizophrenia, autism, and developmental delay. J Med Genet 2010;47:223–229.
  28. D’Angelo CS, Da Paz JA, Kim CA, Bertola DR, Castro CI, Varela MC, Koiffmann CP: Prader-Willi-like phenotype: investigation of 1p36 deletion in 41 patients with delayed psychomotor development, hypotonia, obesity and/or hyperphagia, learning disabilities and behavioral problems. Eur J Med Genet 2006;49:451–460.
  29. De Pater JM, Poot M, Beemer FA, Bijlsma JB, Hack WW, Van Dam WM, Eleveld MJ, Loneus WH, Engelen JJ: Virilization of the external genitalia and severe mental retardation in a girl with an unbalanced translocation 1;18. Eur J Med Genet 2006;49:19–27.
  30. Chen E, Obolensky E, Rauen KA, Shaffer LG, Li X: Cytogenetic and array CGH characterization of de novo 1p36 duplications and deletion in a patient with congenital cataracts, hearing loss, choanal atresia, and mental retardation. Am J Med Genet A 2008;146A: 2785–2790.
  31. Isidor B, Le Cunff M, Boceno M, Boisseau P, Thomas C, Rival JM, David A, Le Caignec C: Complex constitutional subtelomeric 1p36.3 deletion/duplication in a mentally retarded child with neonatal neuroblastoma. Eur J Med Genet 2008;51:679–684.
  32. Lu W, Volcik K, Zhu H, Wen S, Shaw GM, Lammer EJ, Finnell RH: Genetic variation in the proto-oncogene SKI and risk for orofacial clefting. Mol Genet Metab 2005;86:412–416.
  33. Gajecka M, Yu W, Ballif BC, Glotzbach CD, Bailey KA, Shaw CA, Kashork CD, Heilstedt HA, Ansel DA, Theisen A, Rice R, Rice DP, Shaffer LG: Delineation of mechanisms and regions of dosage imbalance in complex rearrangements of 1p36 leads to a putative gene for regulation of cranial suture closure. Eur J Hum Genet 2005;13:139–149.
  34. Schultz D, Litt M, Smith L, Thayer M, McCormack K: Localization of two potassium channel β-subunit genes, KCNA1B and KCNA2B. Genomics 1996;31:389–391.
  35. Emberger W, Windpassinger C, Petek E, et al: Assignment of the human GABAA receptor δ-subunit gene (GABRD) to chromosome band 1p36.3 distal to marker NIB1364 by radiation hybrid mapping. Cytogenet Cell Genet 2000;89:281–282.
  36. Fitzgibbon GJ, Clayton-Smith J, Banka S, Hamilton SJ, Needham MM, Dore JK, Miller JT, Pawson GD, Gaunt L: Array comparative genomic hybridisation-based identification of two imbalances of chromosome 1p in a 9-year-old girl with a monosomy 1p36-related phenotype and a family history of learning difficulties: a case report. J Med Case Reports 2008;2:355.
  37. Suh PG, Park J, Manzoli L, Cocco L, Peak JC, Katan M, Fukami K, Kataoka T, Yuk S, Ryu SH: Multiple roles of phosphoinositide-specific phospholipase C isozymes. BMB Rep 2008;41:415–434.
  38. Cockcroft S: The latest phospholipase C, PLCη, is implicated in neuronal function. Trends Biochem Sci 2006;31:4–7.
  39. Stewart AJ, Mukherjee J, Roberts SJ, Lester D, Farquharson C: Identification of a novel class of mammalian phosphoinositol-specific phospholipase C enzymes. Int J Mol Med 2005;15:117–121.
  40. Nakahara M, Shimozawa M, Nakamura Y, Irino Y, Morita M, Kudo Y, Fukami K: A novel phospholipase C, PLCη2, is a neuron-specific isozyme. J Biol Chem 2005;280:29128–29134.
  41. Kanemaru K, Nakahara M, Nakamura Y, Hashiguchi Y, Kouchi Z, Yamaguchi H, Oshima N, Kiyonari H, Fukami K: Phospholipase C-η2 is highly expressed in the habenula and retina. Gene Expr Patterns 2010;10:119–126.
ppt logo Download Images (.pptx)


Figures
Thumbnail

Tables