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Projeto de investigação
Novel genes causing Familial Hypercholesterolaemia
Financiador
Autores
Publicações
Characterization of the First PCSK9 Gain of Function Homozygote
Publication . Alves, Ana Catarina; Etxebarria, Aitor; Medeiros, Ana Margarida; Benito-Vicente, Asier; Thedrez, Aurélie; Passard, Maxime; Croyal, Mikaël; Martin, Cesar; Lambert, Gilles; Bourbon, Mafalda
Gain of function (GOF) mutations in proprotein convertase subtilisin kexin type 9 (PCSK9) are a rare cause of familial hypercholesterolemia (FH). We identified a child with a clinical diagnosis of FH with 2 novel putative PCSK9 GOF missense variants (p.[(Ala62Asp)]; [(Pro467Ala)]), and no mutation in the low-density lipoprotein (LDL) receptor (LDLR) or in apolipoprotein B100 (APOB) genes. The proband was referred to the Portuguese FH Study (1) at age 11 and presented a total cholesterol of 316 mg/dl and low-density lipoprotein cholesterol (LDL-C) of 234 mg/dl on a strict diet. The phenotype presented by all PCSK9 heterozygous carriers within this large pedigree is similar to APOB heterozygous carriers (LDL-C, 198.75 ± 14.98 mg/dl vs. LDL-C, 211.57 ± 42.02 mg/dl; p = 0.227) but significantly different than heterozygous LDLR carriers (LDL-C, 198.75 ± 14.98 mg/dl vs. LDL-C, 230.63 ± 76.50 mg/dl; p = 0.012) when comparing the relatives’ phenotype in our cohort.
Functionally characterization of the most common LDLR missense alterations found in Portuguese FH patients
Publication . Alves, A.C.; Azevedo, S.; Benito-Vicente, A.; Etxebarria, A.; Barros, P.; Medeiros, A.M.; Martín, C.; Bourbon, Mafalda
Aims: Mutations
in
the
LDLR
gene
are
the
major
cause
of
familial
hypercholesterolaemia
(FH),
which
results
in
defective
catabolism
of
LDL
leading
to
premature
coronary
heart
disease.
Presently,
more
than
1700
different
mutations
in
the
LDLR
gene
have
been
described
as
causing
FH
but
the
majority
of
them
remain
without
functional
characterization.
In
the
Portuguese
Familial
Hypercholesterolemia
Study
(PFHS),
123
LDLR
alterations
were
found
in
243
index
patients
and
their
relatives
up
to
date.
Until
now,
70
of
these
alterations
already
have
a
final
classification
of
pathogenic
and
15
have
been
proved
by
in
vitro
studies
to
be
non-pathogenic.
The
aim
of
the
present
work
is
to
functionally
characterize
16
LDLR
missense
alterations
found
in
Portuguese
FH
patients
and
worldwide.
Genetic Screening of Familial Hypercholesterolemia in Portugal
Publication . Medeiros, A.M.; Alves, A.C.; Bourbon, Mafalda
Purpose: Familial hypercholesterolemia (FH) is a common autosomal dominant
disorder of lipid metabolism (1:500 frequency), caused by mutations in
LDLR, APOB, PCSK9 genes. FH patients have high levels of plasma
cholesterol since birth, accelerated atherosclerosis and, without
treatment, increased risk of premature coronary heart disease (pCHD).
WHO recommends universal screening of FH, since there is a
definite/genetic diagnosis and pharmacological treatment that reduces
patients’ cardiovascular risk. Portugal doesn’t have a national screening
programme for FH but, in 1999, it was established the Portuguese FH
Study (PFHS) that aims to determine prevalence/distribution of FH in
Portugal in order to promote the early identification and characterization
of FH patients and improve their prognosis.
Further evidence of novel APOB mutations as a cause of Familial Hypercholesterolemia
Publication . Alves, A.C.; Etxebarria, A; Benito-Vicente, A.; Martin, C.; Bourbon, Mafalda
Familial hypercholesterolaemia (FH) is an autosomal dominant disorder of cholesterol metabolism. Loss of function mutations in LDLR and APOB and also gain of function
mutations in PCSK9 have been associated with FH, but mutations in LDLR are the most common cause of FH. Until 2012 only mutations in two small fragments of exon 26
and 29 were described as causing FH. In the last 2 years functional mutations in other fragments of exon 26 and 29 as well as in exon 3 and 22 have been reported in FH
patients. However with Next Generation Sequencing techniques others alterations in fragments not studied in routine diagnosis are being found and need to be functional
characterized.
The main aim of this project was to characterize 2 novel alterations in APOB, exon 19 and 26, in order to identify the genetic cause of the hypercholesterolemia
in these patients.
Genetic Diagnosis of Familial Hypercholesterolaemia: The Importance of an Integrated Analysis of Clinical, Molecular and Functional Data
Publication . Alves, A.C.; Benito-Vicente, A.; Etxebarria, A.; Medeiros, A.M.; Martin, C.; Bourbon, Mafalda
Familial Hypercholesterolaemia (FH) is one of the most common monogenic disorders, being caused mostly by mutations in LDL receptor (LDLR) gene. The high levels of LDL cholesterol presented since birth confers these patients an increased cardiovascular risk. Laboratory techniques have improved greatly recently and new variants are found every day that need to be validated as mutations causing disease for the correct diagnosis of FH.
The aim of this study was to characterize both at the phenotypic and genotypic level, families with a clinical diagnosis of FH and discuss the importance of the integration of clinical, molecular and functional data for the correct diagnosis of these patients.
Unidades organizacionais
Descrição
Palavras-chave
Contribuidores
Financiadores
Entidade financiadora
Fundação para a Ciência e a Tecnologia
Programa de financiamento
3599-PPCDT
Número da atribuição
PTDC/SAU-GMG/101874/2008