Neurofibromatosis type 2 (NF2)

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Neurofibromatosis type 2 (NF2)

Written	1997-09	Jean-Loup Huret
		Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Updated	1998-03	Jean-Loup Huret
		Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Updated	2001-02	James F Gusella
		Molecular Neurogenetics Unit, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA

(Note : for Links provided by Atlas : click)

Identity

Other names Central neurofibromatosis
Bilateral acoustic neurofibromatosis
Bilateral acoustic neurinoma
Bilateral acoustic schwannomas
Atlas_Id 10007

Genes implicated in NF2
Inheritance autosomal dominant with almost complete penetrance; frequency is 3/10⁵ newborns; neomutation represent 50% of cases; variable expressivity from mild disease through life (Gardner type) to severe condition at young age (Wishart type: with more than 3 tumours)

Clinics

Note NF2 is an hamartoneoplastic syndrome; hamartomas are localized tissue proliferations with faulty differenciation and mixture of component tissues; they are heritable malformations that have a potential towards neoplasia

Phenotype and clinics
bilateral vestibular (8th cranial pair) schwannomas; other central or peripheral nerve schwannomas; meningiomas; ependymomas.
hearing loss (average age 20 yrs), tinnitus, imbalance, headache, cataract in 50%, facial paralysis.
café-au-lait spots and cutaneous and peripheral neurofibromas may be present, but far less extensively than in neurofibromatosis type 1

Neoplastic risk NF2 cases represent about 5 % of schwannomas and meningiomas (i.e. risk increased by 2000), appearing at the age of 20, while they are found in the general population at the age of 50 and over

Prognosis these tumours are usually benign, but their location within the central nervous system gives them a grave prognosis; patients with the Wishart severe form usually do not survive past 50 yrs

Cytogenetics

Inborn conditions normal

Cytogenetics of cancer chromosome 22 loss is very frequent both in sporadic and in NF2 schwannomas and meningiomas

Genes involved and Proteins

Gene Name NF2 (neurofibromatosis 2)

Location 22q12

DNA/RNA
Description 17 exons (1-15, 17 constitutive, 16 alternatively spliced)

Protein
Description Isoform 1 595 amino acids, isoform 2 590 amino acids (due to inclusion of exon 16 in transcript); contains a FERM domain and a large a helix domain

Expression wide

Function membrane-cytoskeleton anchor; tumour suppressor

Homology band 4.1 family , ezrin, radixin, moesin

Mutations
Germinal germ-line mutations in NF2 patients lead to protein truncation; splice-site or missense mutations are also found; phenotype-genotype correlations are observed (i.e. that severe phenotype are found in cases with protein truncations rather than those with amino acid substitution)

Somatic mutation and allele loss events in tumours in neurofibromatosis type 2 and in sporadic schwannomas and meningiomas are in accordance with the two-hit model for neoplasia

Bibliography

Impaired interaction of naturally occurring mutant NF2 protein with actin-based cytoskeleton and membrane.

Deguen B, Mérel P, Goutebroze L, Giovannini M, Reggio H, Arpin M, Thomas G

Human molecular genetics. 1998 ; 7 (2) : 217-226.

PMID 9425229

Diagnostic issues in a family with late onset type 2 neurofibromatosis.

Evans DG, Bourn D, Wallace A, Ramsden RT, Mitchell JD, Strachan T

Journal of medical genetics. 1995 ; 32 (6) : 470-474.

PMID 7666400

Conditional biallelic Nf2 mutation in the mouse promotes manifestations of human neurofibromatosis type 2.

Giovannini M, Robanus-Maandag E, van der Valk M, Niwa-Kawakita M, Abramowski V, Goutebroze L, Woodruff JM, Berns A, Thomas G

Genes & development. 2000 ; 14 (13) : 1617-1630.

PMID 10887156

Merlin: the neurofibromatosis 2 tumor suppressor.

Gusella JF, Ramesh V, MacCollin M, Jacoby LB

Biochimica et biophysica acta. 1999 ; 1423 (2) : M29-M36.

PMID 10214350

The parental origin of new mutations in neurofibromatosis 2.

Kluwe L, Mautner V, Parry DM, Jacoby LB, Baser M, Gusella J, Davis K, Stavrou D, MacCollin M

Neurogenetics. 2000 ; 3 (1) : 17-24.

PMID 11085592

Advances in neurofibromatosis 2 (NF2): a workshop report.

Lim DJ, Rubenstein AE, Evans DG, Jacks T, Seizinger BG, Baser ME, Beebe D, Brackmann DE, Chiocca EA, Fehon RG, Giovannini M, Glazer R, Gusella JF, Gutmann DH, Korf B, Lieberman F, Martuza R, McClatchey AI, Parry DM, Pulst SM, Ramesh V, Ramsey WJ, Ratner N, Rutkowski JL, Ruttledge M, Weinstein DE

Journal of neurogenetics. 2000 ; 14 (2) : 63-106.

PMID 10992163

The Nf2 tumor suppressor gene product is essential for extraembryonic development immediately prior to gastrulation.

McClatchey AI, Saotome I, Ramesh V, Gusella JF, Jacks T

Genes & development. 1997 ; 11 (10) : 1253-1265.

PMID 9171370

Neurofibromatosis 2 (NF2): clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity.

Parry DM, Eldridge R, Kaiser-Kupfer MI, Bouzas EA, Pikus A, Patronas N

American journal of medical genetics. 1994 ; 52 (4) : 450-461.

PMID 7747758

Germ-line mutations in the neurofibromatosis 2 gene: correlations with disease severity and retinal abnormalities.

Parry DM, MacCollin MM, Kaiser-Kupfer MI, Pulaski K, Nicholson HS, Bolesta M, Eldridge R, Gusella JF

American journal of human genetics. 1996 ; 59 (3) : 529-539.

PMID 8751853

Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2.

Rouleau GA, Merel P, Lutchman M, Sanson M, Zucman J, Marineau C, Hoang-Xuan K, Demczuk S, Desmaze C, Plougastel B

Nature. 1993 ; 363 (6429) : 515-521.

PMID 8379998

Type of mutation in the neurofibromatosis type 2 gene (NF2) frequently determines severity of disease.

Ruttledge MH, Andermann AA, Phelan CM, Claudio JO, Han FY, Chretien N, Rangaratnam S, MacCollin M, Short P, Parry D, Michels V, Riccardi VM, Weksberg R, Kitamura K, Bradburn JM, Hall BD, Propping P, Rouleau GA

American journal of human genetics. 1996 ; 59 (2) : 331-342.

PMID 8755919

A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor.

Trofatter JA, MacCollin MM, Rutter JL, Murrell JR, Duyao MP, Parry DM, Eldridge R, Kley N, Menon AG, Pulaski K

Cell. 1993 ; 72 (5) : 791-800.

PMID 8453669

Citation

This paper should be referenced as such :

Gusella, JF

Neurofibromatosis type 2 (NF2)

Atlas Genet Cytogenet Oncol Haematol. 2001;5(2):150-151.

Free journal version : [ pdf ] [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Tumors/NF2KprID10007.html

History of this paper:

Huret, JL. Neurofibromatosis type 2 (NF2). Atlas Genet Cytogenet Oncol Haematol. 1997;1(1):38-39.

http://documents.irevues.inist.fr/bitstream/handle/2042/32040/09-1997-NF2KprID10007.pdf

Huret, JL. Neurofibromatosis type 2 (NF2). Atlas Genet Cytogenet Oncol Haematol. 1998;2(3):109-110.

http://documents.irevues.inist.fr/bitstream/handle/2042/37447/03-1998-NF2Kpr10007.pdf

External links

OMIM 101000

Orphanet Neurofibromatosis type 2

MeSH D009464  D016518

MedGen D009464  D016518

UMLS C0027832  C0027859

ICD-10 Q85.0

HGMD 120232

Other database Neurofibromatosis Type 2 - GeneClinics

REVIEW articles automatic search in PubMed

Last year articles automatic search in PubMed

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For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.

Other names	Central neurofibromatosis
	Bilateral acoustic neurofibromatosis
	Bilateral acoustic neurinoma
	Bilateral acoustic schwannomas
Atlas_Id	10007
Genes implicated in	NF2
Inheritance	autosomal dominant with almost complete penetrance; frequency is 3/10⁵ newborns; neomutation represent 50% of cases; variable expressivity from mild disease through life (Gardner type) to severe condition at young age (Wishart type: with more than 3 tumours)

Note	NF2 is an hamartoneoplastic syndrome; hamartomas are localized tissue proliferations with faulty differenciation and mixture of component tissues; they are heritable malformations that have a potential towards neoplasia
Phenotype and clinics	bilateral vestibular (8th cranial pair) schwannomas; other central or peripheral nerve schwannomas; meningiomas; ependymomas. hearing loss (average age 20 yrs), tinnitus, imbalance, headache, cataract in 50%, facial paralysis. café-au-lait spots and cutaneous and peripheral neurofibromas may be present, but far less extensively than in neurofibromatosis type 1
Neoplastic risk	NF2 cases represent about 5 % of schwannomas and meningiomas (i.e. risk increased by 2000), appearing at the age of 20, while they are found in the general population at the age of 50 and over
Prognosis	these tumours are usually benign, but their location within the central nervous system gives them a grave prognosis; patients with the Wishart severe form usually do not survive past 50 yrs

Inborn conditions	normal
Cytogenetics of cancer	chromosome 22 loss is very frequent both in sporadic and in NF2 schwannomas and meningiomas

DNA/RNA
Description	17 exons (1-15, 17 constitutive, 16 alternatively spliced)

Protein
Description	Isoform 1 595 amino acids, isoform 2 590 amino acids (due to inclusion of exon 16 in transcript); contains a FERM domain and a large a helix domain
Expression	wide
Function	membrane-cytoskeleton anchor; tumour suppressor
Homology	band 4.1 family , ezrin, radixin, moesin

Mutations
Germinal	germ-line mutations in NF2 patients lead to protein truncation; splice-site or missense mutations are also found; phenotype-genotype correlations are observed (i.e. that severe phenotype are found in cases with protein truncations rather than those with amino acid substitution)
Somatic	mutation and allele loss events in tumours in neurofibromatosis type 2 and in sporadic schwannomas and meningiomas are in accordance with the two-hit model for neoplasia

OMIM	101000
Orphanet	Neurofibromatosis type 2
MeSH	D009464 D016518
MedGen	D009464 D016518
UMLS	C0027832 C0027859
ICD-10	Q85.0
HGMD	120232
Other database	Neurofibromatosis Type 2 - GeneClinics

REVIEW articles	automatic search in PubMed
Last year articles	automatic search in PubMed