2009 Vienna - European Society of Human Genetics

Molecular basis of Mendelian disorders
have been reported worldwide with different impact on the severity of
the disease.
In this study, we characterize the spectrum of the mutations causing
FH in Lebanon, where the incidence of FH is particularly high, presumably
as a result of a founder effect. We confirm the very high frequency
of the LDLR p.Cys681X mutation that accounts for 81.5 % of the FH
Lebanese probands recruited and identify other less frequent mutations
in the LDLR. Finally, we show that the p.Leu21dup, an in frame
insertion of one leucine to the stretch of 9 leucines in exon 1 of PCSK9,
known to be associated with lower LDL-cholesterol levels in general
populations, is also associated with a reduction of LDL-cholesterol levels
in FH patients sharing the p.C681X mutation in the LDLR. Thus,
by studying for the first time the impact of PCSK9 polymorphism on
LDL-cholesterol levels of FH patients carrying a same LDLR mutation,
we show that PCSK9 might constitute a modifier gene in familial
hypercholesterolemia.
P12.059
Heterozygous mutation in mEFV have a potential triallelic effect
on patients with two mutations in mVK gene?
M. Amorini, R. Gallizzi, D. Comito, C. Di Bella, V. Procopio, L. Grasso, F. Pugliatti,
P. Romeo, C. Salpietro, L. Rigoli;
Department of Pediatrics-Policlinico Universitario, Messina, Italy.
Background: Familial Mediterranean Fever (FMF) is an autosomal
recessive disorder characterized by fever and synovial inflammation.
FMF is caused by mutations affecting both alleles of MEFV gene. Hyper-IgD
(HIDS) syndrome is an autosomal recessive disorder characterized
by recurrent episodes of fever associated with lymphadenopathy,
arthralgia, gastrointestinal disturbance, and skin rash. HIDS
is caused by mutations of MVK gene.
Patients and Methods: In our study, we describe a Sicilian (ITALY) patient
with typical symptoms of the FMF. Moreover, he was affected by
an unusual type of HIDS (IgD no detectable). Interesting, the proband
was heterozygote for a mutation of MEFV gene (V726A) and he was
also compound heterozygote for two mutations of MVK gene (V377I,
P228L). The P228L, here described for the first time, is a novel missense
mutation involving the exchange of a proline (CCA), highly conserved
in mammals and birds, with a Leucine (CTA).
Conclusions: The findings of this study encourage our assumptions
about the triallelic transmission of the syndromes associated with periodic
fevers, on the basis of the identification of 3 mutated alleles in
2 different genes. The third mutation in the gene MEFV could play an
epistatic role, modifying the spectrum symptoms of HIDS. Our data
suggest that the study of a HIDS and FMF wider population would be
important not only to clarify the genetic heterogeneity of this group of
syndromes, but mainly to establish a new diagnostic and therapeutic
approach to these patients.
P12.060
Novel FBP1 gene mutations in Arab patients with fructose-1,6bisphosphatase
deficiency.
H. Abalkhail1 , M. Ul-Haque1 , M. Al-Owain1 , F. Al-Dayel1 , Z. Al- Hassnan1 , H.
Al-Zaidan1 , Z. Rahbeeni1 , M. Al-Sayed1 , A. Balobaid1 , A. Cluntun1 , M. Toulimat1 ,
I. Peltekova2 , S. Zaidi3 ;
1King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia,
2 3 Queen’s University, Kingston, ON, Canada, University Health Network, Toronto,
ON, Canada.
Deficiency of fructose-1,6-bisphosphatase (FBP) results in impaired
gluconeogenesis, which is characterized by episodes of hyperventilation,
apnea, hypoglycemia, and metabolic and lactic acidosis. This
autosomal recessive disorder is caused by mutations in the FBP1
gene, which encodes for fructose-1,6-bisphosphatase 1 (FBP1). Although
FBP1 gene mutations have been described in FBP deficient
individuals of various ethnicities, there has been limited investigation
into the genetics of this disorder in Arab patients. This study employed
five consanguineous Arab families, in which seventeen patients were
clinically diagnosed with FBP deficiency. Seven patients and six carrier
parents were analyzed for mutations in the FBP1 gene. DNA sequencing
of the FBP1 gene identified two novel mutations in these families.
A novel six nucleotide repetitive insertion, c114_119dupCTGCAC, was
identified in patients from three families. This mutation encodes for a
duplication of two amino acids (p.Cys39_Thr40dup) in the N-terminal
domain of FBP1. A novel nonsense c.841G>T mutation encoding for
a p.Glu281X truncation in the active site of FBP1 was discovered in
patients from two families. The newly identified mutations in the FBP1
gene are predicted to produce FBP1 deficiency. These mutations are
the only known genetic causes of FBP deficiency in Arab patients. The
p.Cys39_Thr40dup is the first reported amino acid duplication in FBP
deficiency patients. We conclude that this study provides a strong rationale
for genetic testing of FBP deficient patients of Arab ethnicity for
recurrent or novel mutations in the FBP1 gene.
P12.061
Association of the neonatal Fc receptor gene VNtR
polymorphism with primary defects of antibody production
B. Ravcukova 1 , L. Grodecka 1 , J. Nejedlik 1 , M. Plotena 1 , J. Litzmann 2 , T. Freiberger
3 ;
1 Centre for Cardiovascular Surgery and Transplantation, Brno, Czech Republic,
2 Institute of Clinical Immunology and Allergology, St. Anne’s University Hospital
and Masaryk University, Brno, Czech Republic, 3 Centre for Cardiovascular
Surgery and Transplantation,Institute of Clinical Immunology and Allergology,
St. Anne’s University Hospital and Masaryk University, Brno, Czech Republic.
Introduction: The neonatal Fc receptor (FcRn) for IgG has been characterized
in the transfer of passive humoral imunity from mother to fetus.
It transports IgG from maternal circulation to the fetal capillaries of
the placenta villi. Moreover, FcRn protects IgG from degradation and
thus prolongs a half-life of IgG antibodies in the serum. A variable number
of tandem repeats (VNTR) polymorphism in the promoter region
of the FcRn gene has recently been described. Allele *2 showed decreased
promoter activity resulting in lower expression and decreased
monocyte binding capacity for IgG compared to wild type allele *3.
Material and methods: We analysed a distribution of the FcRn gene
VNTR polymorphism in 202 samples of general Czech population,
61 common variable immunodeficiency (CVID) patients, 21 X-linked
agammaglobulinemia (XLA) patients, and 5 individuals with low IgG
but normal IgA levels, using PCR. Fisher exact test was used for statistical
analysis.
Results and discussion: The allele *2 was significantly more frequent
in patients with primary hypogammaglobulinemia compared to general
population (11.5% v.s. 6.2%, p=0.02). While its frequency in CVID patients
did not differ from controls (8.2%, p=0.28), significantly more carriers
of this allele were detected among XLA patients and patients with
low IgG and normal IgA levels (16.7%, p=0.02, and 30.0%, p=0.02,
respectively). More data are needed to better characterize a potential
role of the FcRn gene VNTR polymorphism in disease manifestation
in particular subgroups of patients with primary defects of antibody
production.
Supported by grant IGA-MZ-CR NR9192-3.
P12.062
Congenital factor XIII deficiency caused by the same mutation in
five Tunisian families
N. Louhichi1 , F. Yaïch1 , M. Medhaffar2 , M. Elloumi2 , F. Fakhfakh1 ;
1 2 (1) Human Molecular Genetic Laboratory, Sfax, Tunisia, (2) Service of hematology,
Sfax, Tunisia.
Inherited factor XIII (FXIII) deficiency is a rare bleeding disorder that
can present with umbilical bleeding during the neonatal period, delayed
soft tissue bruising, mucosal bleeding spontaneous intracranial
hemorrhage and soft tissue hemorrhages. Congenital FXIII deficiency
is an autosomal recessive disorder, usually attributed to a defect in the
FXIII A and B subunits coding by F13A and F13B genes respectively.
The aim of this study was to determine the molecular defects responsible
of congenital deficiency of factor XIII in five Tunisian families.
Our diagnoses included antigen determination of FXIII A and B subunits
in both plasma and platelets. Molecular analysis was performed
by direct DNA sequencing of polymerase chain reaction amplified fragments
spanning the coding regions and splice junctions of the FXIII A
subunit gene (F13A) in probands and in families’ members and compared
with the reported sequence of this gene.
The measurement of the A and the B antigen levels showed that, in
all cases, FXIII A was undetectable and FXIII B was within the normal
range. Direct sequencing of the F13A gene for all probands showed
the same “c.869 insC” mutation. This is a frame shift mutation leading
to a null allele. In addition to this mutation three new polymorphisms
had been identified.
We describe here the molecular abnormality found in five Tunisian pro-