Brief Communication

Decreased binding of [¹¹C]flumazenil in Angelman syndrome patients with GABA_A receptor β₃ subunit deletions

Corresponding Author

Irma E. Holopainen MD, PhD

[email protected]

Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland

Department of Pediatric Neurology, University Hospital of Turku, Turku, Finland

Department of Pharmacology and Clinical Pharmacology, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, FinlandSearch for more papers by this author

E.-Liisa Metsähonkala MD,

E.-Liisa Metsähonkala MD

Department of Pediatric Neurology, University Hospital of Turku, Turku, Finland

Search for more papers by this author

Hannaleena Kokkonen MD,

Hannaleena Kokkonen MD

Department of Clinical Genetics, University Hospital of Oulu, Oulu

Search for more papers by this author

Riitta K. Parkkola MD,

Riitta K. Parkkola MD

Department of Diagnostic Radiology, University Hospital of Turku, Turku, Finland

Search for more papers by this author

Tuula E. Manner MD,

Tuula E. Manner MD

Department of Anesthesia, University Hospital of Turku, Turku, Finland

Search for more papers by this author

Kjell Någren PhD,

Kjell Någren PhD

Turku PET Centre, Turku, Finland

Search for more papers by this author

Esa R. Korpi MD, PhD,

Esa R. Korpi MD, PhD

Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland

Search for more papers by this author

Irma E. Holopainen MD, PhD,

Corresponding Author

Irma E. Holopainen MD, PhD

[email protected]

Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland

Department of Pediatric Neurology, University Hospital of Turku, Turku, Finland

Department of Pharmacology and Clinical Pharmacology, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, FinlandSearch for more papers by this author

E.-Liisa Metsähonkala MD,

E.-Liisa Metsähonkala MD

Department of Pediatric Neurology, University Hospital of Turku, Turku, Finland

Search for more papers by this author

Hannaleena Kokkonen MD,

Hannaleena Kokkonen MD

Department of Clinical Genetics, University Hospital of Oulu, Oulu

Search for more papers by this author

Riitta K. Parkkola MD,

Riitta K. Parkkola MD

Department of Diagnostic Radiology, University Hospital of Turku, Turku, Finland

Search for more papers by this author

Tuula E. Manner MD,

Tuula E. Manner MD

Department of Anesthesia, University Hospital of Turku, Turku, Finland

Search for more papers by this author

Kjell Någren PhD,

Kjell Någren PhD

Turku PET Centre, Turku, Finland

Search for more papers by this author

Esa R. Korpi MD, PhD,

Esa R. Korpi MD, PhD

Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland

Search for more papers by this author

First published: 16 January 2001

https://doi.org/10.1002/1531-8249(200101)49:1<110::AID-ANA17>3.0.CO;2-T

Citations: 45

Share a link

Email
Wechat
Bluesky

Abstract

We used positron emission tomography (PET) to study brain [¹¹C]flumazenil (FMZ) binding in four Angelman syndrome (AS) patients. Patients 1 to 3 had a maternal deletion of 15q11-q13 leading to the loss of β3 subunit of γ-aminobutyric acid_A/benzodiazepine (GABA_A/BZ) receptor, whereas Patient 4 had a mutation in the ubiquitin protein ligase (UBE3A) saving the β₃ subunit gene. [¹¹C]FMZ binding potential in the frontal, parietal, hippocampal, and cerebellar regions was significantly lower in Patients 1 to 3 than in Patient 4. We propose that the 15q11-q13 deletion leads to a reduced number of GABA_A/BZ receptors, which could partly explain the neurological deficits of the AS patients. Ann Neurol 2001;49:110–113

References

1 Moncla A, Malzac P, Voelckel M-A, et al. Phenotype-genotype correlation in 20 deletion and 20 non-deletion Angleman syndrome patients. Eur J Hum Genet 1999; 7: 131–139.
10.1038/sj.ejhg.5200258
CAS PubMed Web of Science® Google Scholar
2 Oh CE, McMahon R, Benzer S, et al. bendless, a Drosophila gene affecting neuronal connectivity, encodes a ubiquitin-conjugating enzyme homolog. J Neurosci 1994; 14: 3166–3179.
10.1523/JNEUROSCI.14-05-03166.1994
CAS PubMed Web of Science® Google Scholar
3 Lüddens H, Korpi ER, Seeburg PH. GABA_A/benzodiazepine receptor heterogeneity: neurophysiological implications. Neuropharmacology 1995; 34: 245–254.
10.1016/0028-3908(94)00158-O
PubMed Web of Science® Google Scholar
4 Glatt K, Glatt H, Lalande M. Structure and organization of GABRB3 and GABRA5. Genomics 1997; 41: 63–69.
10.1006/geno.1997.4639
CAS PubMed Web of Science® Google Scholar
5 DeLorey TM, Handforth A, Anagnostaras SG, et al. Mice lacking the β3 subnit of the GABA_A receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome. J Neurosci 1998; 18: 8505–8514.
10.1523/JNEUROSCI.18-20-08505.1998
CAS PubMed Web of Science® Google Scholar
6 Homanics GE, DeLorey TM, Firestone LL, et al. Mice devoid of γ-aminobutyrate type A receptor β₃-subunit have epilepsy, cleft palate, and hypersensitive behavior. Proc Natl Acad Sci USA 1997; 94: 4143–4148.
10.1073/pnas.94.8.4143
CAS PubMed Web of Science® Google Scholar
7 Koepp MJ, Hand KSP, Labbé C, et al. In vivo [¹¹C]flumazenil-PET correlates with ex vivo [³H]flumazenil autoradiography in hippocampal sclerosis. Ann Neurol 1998; 43: 618–626.
10.1002/ana.410430510
CAS PubMed Web of Science® Google Scholar
8 Kokkonen H, Kähkönen M, Leisti J. A molecular and cytogenetic study in Finnish Prader-Willi patients. Hum Genet 1995; 95: 568–571.
10.1007/BF00223871
CAS PubMed Web of Science® Google Scholar
9 Glenn CC, Nicholls RD, Robinson WP, et al. Modification of 15q11–q13 DNA methylation imprints in unique Angelman and Prader-Willi patients. Hum Mol Genet 1993; 2: 1377–1382.
10.1093/hmg/2.9.1377
CAS PubMed Web of Science® Google Scholar
10 Någren K, Halldin C. Methylation of amide and thiol functions with [¹¹C]methyltriflate, as examplified by [¹¹C]NMSP, [¹¹C]flumazenil and [¹¹C]methionine. J Label Comp Rad 1998; 41: 831–841.
10.1002/(SICI)1099-1344(1998090)41:9<831::AID-JLCR129>3.0.CO;2-E
CAS Web of Science® Google Scholar
11 Hume SP, Myers R, Bloomfield PM, et al. Quantitation of carbon-11-labeled raclopride in rat striatum using positron emission tomography. Synapse 1992; 12: 47–54.
10.1002/syn.890120106
CAS PubMed Web of Science® Google Scholar
12 Odano I, Anezaki T, Ohkubo M, et al. Decrease in benzodiazepine receptor binding in a patient with Angelman syndrome detected by iodine-123 iomazenil and single-photon emission tomography. Eur J Nucl Med 1996; 23: 598–604.
10.1007/BF00833400
PubMed Web of Science® Google Scholar
13 Pratt GD, Richter A, Möhler H, et al. Regionally selective and age-dependent alterations in benzodiazepine receptor binding in the genetically dystonic hamster. J Neurochem 1995; 64: 2153–2158.
10.1046/j.1471-4159.1995.64052153.x
CAS PubMed Web of Science® Google Scholar
14 Prevett MC, Lammertsma AA, Brooks DJ, et al. Benzodiazepine-GABA_A receptors in idiopathic generalized epilepsy measured with [¹¹C]flumazenil and positron emission tomography. Epilepsia 1995; 36: 113–121.
10.1111/j.1528-1157.1995.tb00969.x
CAS PubMed Web of Science® Google Scholar
15 Lüddens H, Korpi ER. GABA antagonists differentiate between recombinant GABA_A/benzodiazepine receptor subtypes. J Neurosci 1995; 15: 6957–6962.
CAS PubMed Web of Science® Google Scholar
16 Ben-Ari Y, Khazipov R, Leinekugel X, et al. GABA_A, NMDA and AMPA receptors: a developmentally regulated “ménage à trois”. Trends Neurosci 1997; 20: 523–529.
10.1016/S0166-2236(97)01147-8
CAS PubMed Web of Science® Google Scholar
17 Laurie DJ, Wisden W, Seeburg PH. The distribution of thirteen GABA_A receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development. J Neurosci 1992; 12: 4151–4172.
10.1523/JNEUROSCI.12-11-04151.1992
CAS PubMed Web of Science® Google Scholar

Citing Literature

Volume49, Issue1

January 2001

Pages 110-113

Decreased binding of [¹¹C]flumazenil in Angelman syndrome patients with GABA_A receptor β₃ subunit deletions

Abstract

References

Citing Literature

References

Information

About Wiley Online Library

Help & Support

Opportunities

Connect with Wiley

Decreased binding of [11C]flumazenil in Angelman syndrome patients with GABAA receptor β3 subunit deletions

Abstract

References

Citing Literature

References

Related

Information

Decreased binding of [¹¹C]flumazenil in Angelman syndrome patients with GABA_A receptor β₃ subunit deletions