dc.contributor.author
Girisha, Katta Mohan
dc.contributor.author
Bidchol, Abdul Mueed
dc.contributor.author
Graul-Neumann, Luitgard
dc.contributor.author
Gupta, Ashish
dc.contributor.author
Hehr, Ute
dc.contributor.author
Lessel, Davor
dc.contributor.author
Nader, Sean
dc.contributor.author
Shah, Hitesh
dc.contributor.author
Wickert, Julia
dc.contributor.author
Kutsche, Kerstin
dc.date.accessioned
2018-06-08T03:55:19Z
dc.date.available
2016-04-28T07:37:19.784Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/16204
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-20388
dc.description.abstract
Background Larsen syndrome is an autosomal dominant skeletal dysplasia
characterized by large joint dislocations and craniofacial dysmorphism. It is
caused by missense or small in-frame deletions in the FLNB gene. To further
characterize the phenotype and the mutation spectrum of this condition, we
investigated seven probands, five sporadic individuals and a mother-son-duo
with Larsen syndrome. Methods The seven patients from six unrelated families
were clinically and radiologically evaluated. All patients were screened for
mutations in selected exons and exon-intron boundaries of the FLNB gene by
Sanger sequencing. FLNB transcript analysis was carried out in one patient to
analyse the effect of the sequence variant on pre-mRNA splicing. Results All
patients exhibited typical facial features and joint dislocations. Contrary to
the widely described advanced carpal ossification, we noted delay in two
patients. We identified the five novel mutations c.4927G > A/p.(Gly1643Ser),
c.4876G > T / p.(Gly1626Trp), c.4664G > A / p.(Gly1555Asp), c.2055G > C /
p.Gln685delins10 and c.5021C > T / p.(Ala1674Val) as well as a frequently
observed mutation in Larsen syndrome [c.5164G > A/p.(Gly1722Ser)] in the
hotspot regions. FLNB transcript analysis of the c.2055G > C variant revealed
insertion of 27 bp intronic sequence between exon 13 and 14 which gives rise
to in-frame deletion of glutamine 685 and insertion of ten novel amino acid
residues (p.Gln685delins10). Conclusions All seven individuals with Larsen
syndrome had a uniform clinical phenotype except for delayed carpal
ossification in two of them. Our study reveals five novel FLNB mutations and
confirms immunoglobulin-like (Ig) repeats 14 and 15 as major hotspot regions.
The p.Gln685delins10 mutation is the first Larsen syndrome-associated
alteration located in Ig repeat 5. All mutations reported so far leave the
filamin B protein intact in accordance with a gain-of-function effect. Our
findings underscore the characteristic clinical picture of FLNB-associated
Larsen syndrome and add Ig repeat 5 to the filamin B domains affected by the
clustered mutations.
en
dc.rights.uri
http://creativecommons.org/licenses/by/4.0/
dc.subject
Larsen syndrome
dc.subject
Gain-of-function
dc.subject
Autosomal-dominant
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit
dc.title
Phenotype and genotype in patients with Larsen syndrome
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation
BMC Medical Genetics. - 17 (2016), 27
dc.title.subtitle
clinical homogeneity and allelic heterogeneity in seven patients
dcterms.bibliographicCitation.doi
10.1186/s12881-016-0290-6
dcterms.bibliographicCitation.url
http://bmcmedgenet.biomedcentral.com/articles/10.1186/s12881-016-0290-6
refubium.affiliation
Charité - Universitätsmedizin Berlin
de
refubium.mycore.fudocsId
FUDOCS_document_000000024440
refubium.note.author
Der Artikel wurde in einer Open-Access-Zeitschrift publiziert.
refubium.resourceType.isindependentpub
no
refubium.mycore.derivateId
FUDOCS_derivate_000000006343
dcterms.accessRights.openaire
open access