©
1997 Oxford University Press
147-151
Footnote
Marfan Database (second edition): software and database for the analysis of
mutations in the human FBN1 gene
Marfan Database (second edition): software and database for the analysis of mutations in the human FBN1 gene
Each
Gwenaëlle
Collod-Béroud
1
,
Christophe
Béroud
1
,
Lesley
Adès
2
,
Cheryl
Black
3
,
Maureen
Boxer
3
,
David J.
Brock
4
,
Maurice
Godfrey
5
,
Carolyne
Hayward
4
,
Leena
Karttunen
6
,
Dianna
Milewicz
7
,
Leena
Peltonen
6
,
Robert I.
Richards
8
,
Mei
Wang
5
,
Claudine
Junien
1,9
and
Catherine
Boileau
1,9,
*
1
INSERM U383, Hôpital Necker-Enfants Malades, Université René Descartes, Paris V, 149-161 rue de Sèvres, 75743
Paris
Cedex 15,
France
,
2
Department of Medical Genetics, the New Children's Hospital, Parramata 2124,
Sydney
,
Australia
,
3
Molecular Genetics Laboratory, Department of Pathology, Ninewells Hospital and
Medical School,
Dundee
DD1 9SY,
UK
,
4
Human Genetics Unit, Department of Medicine, University of Edinburgh, Western
General Hospital,
Edinburgh
EH4 2XU,
UK
,
5
Department of Pediatrics, Munroe Center for Human Genetics, University of
Nebraska Medical Center,
Ohama
, NE 68198,
USA
,
6
National Public Health Institute, Department of Human Molecular Genetics, FIN-00300
Helsinki
,
Finland
,
7
University of Texas-Houston Medical School, Department of Internal Medicine,
Houston
, TX 77030,
USA
,
8
Department of Medical Genetics, Women's and Children's Hospital,
North Adelaide
, SA 5006,
Australia
and
9
Laboratoire Central de Biochimie et de Génétique Moléculaire, CHU Ambroise Paré,
Boulogne
,
France
Received October 2, 1996;
Accepted October 8, 1996
ABSTRACT
Fibrillin is the major component of extracellular microfibrils. Mutations in the
fibrillin gene on chromosome 15 (FBN1) were described at first in the heritable
connective tissue disorder, Marfan syndrome (MFS). More recently, FBN1 has also
been shown to harbor mutations related to a spectrum of conditions
phenotypically related to MFS. These mutations are private, essentially
missense, generally non-recurrent and widely distributed throughout the gene. To date no clear
genotype/phenotype relationship has been observed excepted for the localization
of neonatal mutations in a cluster between exons 24 and 32. The second version
of the computerized Marfan database contains 89 entries. The software has been
modified to accomodate new functions and routines.
Fibrillin, Marfan syndrome and type 1 fibrillinopathies
Fibrillin-1 is a large glycoprotein (320 kDa) ubiquitously distributed in connective
tissues (
1
). It is the major component of 10-12 nm microfibrils of the extracellular matrix (
1
). The fibrillin-1 gene (FBN1) lies on the long arm of chromosome 15 (15q15-q21.1) (
2
) and its entire coding sequence of 2871 amino acids is known (
3
-
5
). It contains 65 exons encoding a multidomain and highly repetitive protein:
four `EGF-like' modules [domains with homology to a module found in human epidermal
growth factor (EGF) precursor], 43 `cb EGF-like' modules (EGF-like domain presenting a calcium-binding consensus sequence), seven `8-cysteine' modules (that are homologous with transforming-growth factor-[beta]1 binding-protein), two `hybrid' modules
that combine features of the two former, a `NH2 Unique region' (unique N-terminal stretch of basic residues), a `proline rich domain' and the `COOH
unique region' (
4
,
5
). Mutations in the FBN1 gene are associated with a spectrum of overlapping
diseases named type 1 fibrillinopathies: complete and incomplete Marfan
syndrome (
6
-
9
,
11
-
17
,
23
-
26
,
29
,
36
,
39
,
41
), severe neonatal Marfan syndrome (
15
,
20
,
22
,
26
,
31
-
32
,
38
,
41
), dominantly inherited ectopia lentis (
15
,
18
,
36
), isolated skeletal features of MFS (
18
,
21
,
28
) and the Shprintzen-Goldberg syndrome (
34
).
The Marfan database
Table 1
Each line represents a single FBN1 mutation. The columns contain the following
information and abbreviations:
Column A:
File number.
Column B:
Exon number at which the mutation is located.
Column C:
Nucleotide position at which the mutation is located.
Column D:
Codon number at which the mutation is located.
Column E:
Normal base sequence of the codon in which the mutation occurred.
Column F:
Mutated base sequence of the codon in which the mutation occurred.
Column G:
Concerns base substitutions. It gives the base change, by convention, read from
the coding strand. If the mutation predicts a premature protein-termination, the novel stop codon position is given, e.g. `Stop at 2115'.
Column H:
Mutation name according to Beaudet
et al
. (44).
Column I:
Wild type amino acid.
Column J:
Mutant amino acid. Deletion and insertion mutations which result in a
frameshift are designated by `Frameshift'. Nonsense mutations are designated by
`Stop'.
Column K:
Protein domain in which the mutation occurs. Each motif group is numbered
separately and according to their position with respect to the N-terminal end of the protein, e.g. `cb EGF-like' (for calcium-binding EGF-like motifs) #1-43, `EGF-like' (for non calcium-binding EGF-like motifs) #1-4, `8-cys' (for `8-cysteine' motifs) #1-7,
`Hybrid motifs' #1 and 2 (3-5).
Column L-Q:
Diagnostic manifestations in the systems listed by Beighton
et al
. (45) and De Paepe
et al
. (46). In all these columns, `?' indicates either lack of or unspecified data
until more precise information is available.
Column L:
Presence (+) or absence (-) of skeletal manifestations.
Column M:
Presence (+) or absence (-) of ocular manifestations.
Column N:
Presence (+) or absence (-) of cardiovascular manifestations.
Column O:
Presence (+) or absence (-) of pulmonary manifestations.
Column P:
Presence (+) or absence (-) of manifestations in skin and integument.
Column Q:
Presence (+) or absence (-) of manifestations in central nervous system.
Column R:
Reference number indicating the publication in which the mutation is described.
NP indicates unpublished mutations contributed by NP1 (M. Boxer and C. Black)
and NP2 (D. Milewicz). P indicates references that are in press.
The database below lists known point mutations, deletions or insertions, and
splice mutations in the gene FBN1. Its purpose is to update that of last year (
43
) by collecting in a standardized, accessible and summary form the molecular and
the clinical data on the causative mutations of Marfan syndrome and type 1
fibrillinopathies. The present version of the database contains 89 entries
corresponding to mutations either published or only reported in meeting
proceedings or contributed by the co-authors of this paper (Table
4
). It is not intented to replace primary publications, although it does contain
unpublished data. As in the previous edition, mutation names are given
according to Beaudet
et al
. (
44
) and numbered with respect to the FBN1 gene cDNA sequence obtained from the
GenBank database (GenBank database accession number L13923; complete coding
sequence of HUM-FIBRILLIN Homo sapiens fibrillin mRNA). For each mutation, information is
provided at several levels: at the gene level (exon and codon number, wild type
and mutant codon, mutational event, mutation name), at the protein level (wild
type and mutant amino acid, affected domain) and at the clinical level (absence
or presence of skeletal, ocular, cardiovascular, central nervous system and
other various manifestations). The clinical data are entered with respect to
the nosology proposals of Beighton
et al
. (
45
) recently revised by De Paepe
et al
. (
46
). We have included repeat observations of the same mutation. Seven recurrent
mutations have been reported either twice (R122C, R627C, G1013R, R1137P and
C1223Y) or thrice (E1073K and 5788 +5 G -> A). Since the present version of the software cannot accomodate two
mutational events in a given individual three mutations are not included in the
current version of the database: the double mutant Splice exon 51 and X2113X
reported by Dietz
et al
. (
10
), the compound deletion del3901-4; 3908-9
reported by Nijbroek
et al
. (
26
), and the double mutant I1071S and E1073D reported by Wang
et al
. (
42
). A fourth mutation is not included in the Marfan database: the 1588 +21 G -> A (
37
) until more precise information is available on mRNA splicing or stability.
Newly developed software routines
The sofware package contains routines for the analysis of the FBN1 database that
were developped with the 4
th
dimension
®
(4D) package from ACI. The purpose of the software is to facilitate the
mutational analysis of the FBN1 gene at the molecular level and to provide the
tools to search for genotype/phenotype correlations. Initially, six specific
routines were developed (
43
). Three new routines have been added to the software: (i) `Restriction enzyme'
appears on the first page of the mutation file. If the mutation modifies a
restriction site, the program shows a restriction map displaying the new or
abolished site and the enzymes of interest. (ii) `Amino acid type search'
studies the mutations with respect to phylogenetic conservation. In effect, the
fibrillin gene has been identified and sequenced in two mammalian species
[complete coding sequence of mouse fibrillin (Fbn-1) mRNA and complete coding sequence of bovine fibrillin (BovFib] mRNA,
GenBank database accession numbers L29454 and L28748 respectively). The
identity at the amino level between the human and bovine sequences is 97.8% and
between the human and the mouse sequences of 96.2%. Therefore, the routine
lists the mutations affecting non-conserved amino acids in the bovine, in the mouse, or in both sequences.
(iii) `Binary comparison' compares two mutation groups, each group being
defined by distinct research criteria chosen from the database (molecular,
clinical, age of onset, sex . . . ). The result can be displayed as either of
several graphic representations (by amino acids, by exon, or by protein domain)
of the distribution of the sorted mutations. Furthermore the sorted mutations
can appear in a cumulated or detailed format (insertion, deletion, missense,
nonsense).
Finally, an overall modification of the software has been made to enable the
simultaneous study of several routines or multicriteria researches.
Database update and software availability
The current database and subsequent updated versions are available on request to
G.C. or C.Boil. on floppy disc using Apple format and Microsoft Excel
®
, or by e-mail (collod{at}ceylan.necker.fr). Notification of omissions and errors in the current version as well as
specific phenotypic data would be gratefully received by the corresponding
author.
The software package is available on a collaborative basis. It will soon be
available on the Internet. The software will be expanded as the database grows
and according to the requirements of its users. New functions could be
implemented.
ACKNOWLEDGEMENTS
This work was supported by grants from GREG (Groupe de Recherche et d'Etude du Génome), Fondation de France, Recherche Clinique-Assistance Publique Hôpitaux de Paris (Grant CRC940116), AFM (Association Française contre les Myopathies), Université René Descartes-Paris V, Ministère de l'Education
Nationale, de l'Enseignement Supérieur, de la Recherche et de l'Insertion Professionnelle (ACC-SV2) and Faculté de Médecine Necker. G.C. is supported by a grant from
Société de Secours des Amis des Sciences.
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*
To whom correspondence should be addressed at: INSERM UR383, Hôpital Necker-Enfants Malades, Clinique Maurice Lamy, 149-161 rue de Sèvres, 75743 Paris Cedex 15, France. Tel: +33 1 44 49
44 84/83; Fax: +33 1 47 83 32 06; Email: boileau@ceylan.necker.fr
