Review on GLMN (glomulin), with data on DNA, on the protein encoded, and where the gene is implicated

Aerts, V

Boon, LM

Brouillard, P

Vikkula, M

Atlas of Genetics and Cytogenetics in Oncology and Haematology

I-Revues

 
 
 
 
 
 
Gene Section 
Mini Review 
 
Atlas Genet Cytogenet Oncol Haematol. 2008;12(1)  41 
Atlas of Genetics and Cytogenetics 
in Oncology and Haematology                         
                         OPEN ACCESS JOURNAL AT INIST-CNRS 
GLMN (glomulin) 
Virginie Aerts, Pascal Brouillard, Laurence M Boon, Miikka Vikkula 
Human Molecular Genetics (GEHU) de Duve Institute, Universite catholique de Louvain, Avenue 
Hippocrate 74(+5), bp. 75.39, B-1200 Brussels, Belgium 
Published in Atlas Database: July 2007 
Online updated version: http://AtlasGeneticsOncology.org/Genes/GLMNID43022ch1p22.html  
DOI: 10.4267/2042/38473 
 
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. 
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology 
 
Identity 
Other names: GLMN; FAP68; FAP48 
Location: 1p22.1 
Note: The gene was identified by linkage mapping and 
positional cloning. There is no evidence for locus 
heterogeneity. Haplotype sharing has been reported for 
an important number of families. 
DNA/RNA 
Description 
The genomic DNA of the glomulin gene spans about 
55 kbp and contains 19 exons coding for 1785 bp. The 
first exon is non coding, the start codon is located on 
the second exon and the stop codon in the last exon. 
Transcription 
In all human and murine tissues tested, a about 2 kb 
transcript was observed by Northern blot hybridization, 
suggesting that glomulin expression is ubiquitous. This 
could be due to the presence of glomulin-expressing 
blood vessels in the various tissues analysed. 
By in situ hybridisation on murine embryos, glomulin 
expression was evident at embryonic E10.5 days post-
coitum (dpc) and localized to the cardiac outflow trac . 
Between E11.5 to 14.5 dpc, glomulin mRNA is most 
abundant in the walls of large vessels (e.g. dorsal 
aorta). At E14.5 dpc, E16.5 dpc, and in adult tissue , 
expression of glomulin is clearly restricted to vascular 
smooth muscle cells. The high level of glomulin 
expression in the murine vasculature indicates that
glomulin may have an important role in blood vessel 
development and/or maintenance. 
A truncated form of glomulin, called FAP48, with an
altered carboxy-terminal end, was isolated from a 
Jurkat-cell library. However FAP48, which presents  
70% homology with glomulin, was not detected in 
other tissues and cells tested. Thus, it might be an 
aberrant transcript in this library. 
Pseudogene 
In man, no paralogue exists. Yet, a pseudogene is 
located on chromosome 21. It contains only a few 
exons (exons 6 to 10), without intervening introns a d 
with several nucleotide differences. Thus, glomulin 
seems to be unique in the human genome. 
Protein 
Note: Glomulin was identified by reverse genetics, and 
its function is currently unknown. 
Description 
Glomulin gene encodes a protein of 594 amino acids 
(68 kDa). In silico analysis reveals no known 
functional or structural domains, but a few potential 
phosphorylation and glycosylation sites. 
Expression 
(see above, para Transcription). 
Localisation 
By in silico analysis, no signal sequence or clear 
transmembrane domain in glomulin has been identified. 
Glomulin (FAP68) is likely an intracellular protein. 
Function 
The exact function of glomulin is unknown. 
Glomulin (under the name of FAP48) has been 
described to interact with FKBP12, an immunophilin 
that binds the immunosuppressive drugs FK506 and 
rapamycin. FKBP12 interacts with the TGFbeta type I 
receptor, and prevents its phosphorylation by the typ  
II receptor in the absence of TGFbeta. Thus, FKBP12 
safeguards against the ligand-independent activation of  
 
GLMN (glomulin) Aerts V et al 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2008;12(1)  42 
this pathway. Glomulin, through its interaction with  
FKBP12, could act as a repressor of this inhibition. 
Glomulin has also been described to interact with the 
last 30 amino acids of the C-terminal part of the HGF 
receptor, c-MET. This receptor is a transmembrane 
tyrosine kinase, which becomes tyrosine-
phosphorylated upon activation by HGF. Glomulin 
interacts with the inactive, non phosphorylated form of 
c-MET. When c-MET is activated by HGF, glomulin is 
released in a phosphorylated form. This leads to p70 S6 
protein kinase (p70S6K) phosphorylation. This 
activation occurs synergistically with the activation by 
the c-MET-activated PI3 kinase. It is not known 
whether glomulin activates p70S6K directly or 
indirectly. The p70S6K is a key regulator of protein 
synthesis. Glomulin could thereby control cellular 
events such as migration and cell division. 
The third reported glomulin partner is Cul7, a Cul1 
homologue. This places glomulin in an SCF-like 
complex, which is implicated in protein ubiquitination 
and degradation. 
Homology 
Glomulin seems to be an unique protein. No paralogue 
has been found and its lack in GVM is not compensated 
by another protein. Orthologues of glomulin have ben 
identified in other species (cat, chimpanzee, cow, dog, 
mouse, rat, rhesus macaque, xenopus, zebrafish) and 
thus it is present in all vertebrates but not in insects or 
bacteries. 
Mutations 
Note: There is no phenotype-genotype correlation in 
GVM. 
Germinal 
To date, 29 different inherited mutations (deletions, 
insertions and nonsense substitutions) have been 
identified. The most 5' mutation are located in the first 
coding exon. The majority of them cause premature 
truncation of the protein and likely result in loss-of-
function. One mutation deletes 3 nucleotides resulting 
in the deletion of an asparagine at position 394 of the 
protein. 
More than 70% of GVMs are caused by eight different 
mutations in glomulin: 157delAAGAA (40,7%), 
108C>A (9,3%), 1179delCAA (8,1%), 421insT and 
738insT (4,65% each), 554delA+556delCCT (3,5%), 
107insG and IVS5-1(G>A) (2,3% each). 
Somatic 
The phenotypic variability observed in GVM could be 
explained by the need of a somatic second-hit mutation. 
Such a mechanism was discovered in one GVM 
(somatic mutation 980delCAGAA), suggesting that the 
lesion is due to a complete localized loss-of-function of 
glomulin. This concept can explain why some patients 
have bigger lesions than others, why new lesions 
appear, and why they are multifocal. This could also 
explain, why some mutation carriers are unaffected. 
 
Schematic representation of glomulin: The two stars (*) indicate the start and the stop codons, in exon 2 and 19 respectively. All known 
mutations are shown. Somatic second hit is in blue. 
 
 
 
 
 
 
 
 
 
 
GLMN (glomulin) Aerts V et al 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2008;12(1)  43 
Implicated in 
Glomuvenous malformation (GVM) 
Note: GVM is often, if not always, hereditary, and 
transmitted as an autosomal dominant disorder. 
Disease 
GVM is a localized bluish-purple cutaneous vascular 
lesion, histologically consisting of distended venous 
channels with flattened endothelium surrounded by 
variable number of maldifferentiated smooth muscle-
like 'glomus cells' in the wall. GVM account for 5% of 
venous anomalies referred to centers for vascular 
anomalies. 
Seven features characterize GVM lesions: (1) Colour: 
GVMs can be pink in infants, the most are bluish-
purple; (2) Affected tissues: the lesions are localized to 
the skin and subcutis; (3) Localization: lesions are more 
often located on the extremities; (4) Appearance: 
lesions are usually nodular and multifocal. They are
often hyperkeratotic; (5) The lesions are not 
compressible; (6) The lesions are painful on palpation; 
(7) New lesions can appear with time, likely after 
trauma. 
GVM has no neoplastic histological characteristics and 
never becomes malignant. 
References 
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and electron microscopic study. Arch Dermatol 
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complexes with both immunophilins FKBP59 and FKBP12. 
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rapamycin. J biol Chem 1996;271(51):32923-32929. 
Chen YG, Liu F, Massague J. TGFbeta receptor inhibition by 
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Boon LM, Brouillard P, Irrthum A, Karttunen L, Warman ML, 
Rudolph R, Mulliken JB, Olsen BR, Vikkula M. A gene for 
inherited cutaneous venous anomalies ('glomangiomas') 
localizes to chromosome 1p21-22. Am J Hum Genet 
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This article should be referenced as such: 
Aerts V, Brouillard P, Boon LM, Vikkula M. GLMN (glomulin). 
Atlas Genet Cytogenet Oncol Haematol.2008;12(1):41-43.  
 
 


GLMN (glomulin)

Aerts, Virginie

Brouillard, Pascal

Boon, Laurence M.

Vikkula, Miikka

DIAL UCLouvain

http://documents.irevues.inist.fr/bitstream/2042/38473/2/07-2007-GLMNID43022ch1p22.pdf

GLMN (glomulin)

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