European Human Genetics Conference 2007 June 16 – 19, 2007 ...

Molecular and biochemical basis of disease
crossing over between low copy repeats (LCRs). Paternal occurrence
of similar deletions, instead, results in Prader-Willi syndrome (PWS,
OMIM#176270). In PWS no coding mutations have been found in contrast
with UBE3A mutations in AS, suggesting that PWS is caused by
loss of function of multiple genes.
Different sized deletions associated with AS are very rare. To our
knowledge, at least two familial atypical deletions were reported, and
the microdeletions caused AS in maternal inheritance but no PWS features
in paternal inheritance, enabling differentiation of the PWS critical
region (PWSCR) from the AS critical region (ASCR).
We encountered a similar family with an atypical microdeletion, consisting
of an AS boy later confirmed, and asymptomatic mother and
maternal grandfather. All three had an atypical microdeletion. We
could successfully determine deletion breakpoints of the family, and
will discuss about genes responsible for PWS.
P0729. Familial Defective apo B-100 (FDB): founder effect in
a population of the South of Europe and comparison with the
Familial Hypercholestolaemia (FH).
I. Ejarque-Doménech, E. Milián, J. Real, F. Chaves, A. García-García, J. Ascaso,
R. Carmena;
Hospital Clínico Universitario de Valencia, Valencia, Spain.
We have identified a large number of subjects (n=19) with FDB (OMIM
= 144010) due to the R3500Q mutation at APOB gene in a population
of the South of Europe and the 7 th FDB homozygote in the world. This
was possible through identification of the first FDB heterozygous in
Spain. The study of his family and the population of the same geographic
area allowed us to identify the rest of the FDB cohort.
We studied the lipoprotein phenotype of 19 FDBs, and compared it
with the one of subjects with classic FH of the same geographic origin,
taking in account the type of mutations at LDLR gene: null-mutations
TC= 343.7 (69.6), missense mutations affecting binding 3-5 repeat region
TC= 394.4 (47.9), and missense mutations not affecting that binding
region TC= 335.2 (60.2). FDB subjects showed a milder clinical
and lipoprotein phenotype TC= 286.5 (57.9).
We have also studied the founder effect of our FDBs and the history
of that geographic area of the Valencian Region. The analysis of the
haplotype of the gene APOB of our FDBs and historical records of that
geographic zone leads us to conclude that their mutation originated
7000 years ago in the Southwestern region of Germany, between Rhin
and Main rivers.
TC = Total Cholesterol; data expressed in mg/dl with PA) at the amino acid position p.G329R which is highly
conserved within the 15 members of the human GalNAc transferase
family and among species. This residue is situated in the linker region
between the catalytic and the ricin-like domain of GalNAc-T3. In
vitro analysis of FGF23 O-glycosylation by GalNAc-T3(G329R), performed
by MALDI-TOF mass spectrometry, showed lack of GalNAc-
T3(G329R) activity. Previously reported GALNT3 mutations in FTC
have been null mutations or compound heterozygous missense muta-
tions in the catalytic domain. We conclude that the novel missense
mutation of GalNAc-T3 causes FTC.
P0731. A study of FGFR3 gene mutations in brazilian patients
with achondroplasia, hypochondroplasia and thanatophoric
dysplasia
J. M. Pina-Neto, D. Ortolan, W. A. Silva-Jr;
School of Medicine of Ribeirão Preto, Ribeirão Preto, Brazil.
We studied the FGFR3 mutations in 80 brazilian patients with achondroplasia
, 22 with hypochondroplasia and 9 with thanatophoric dysplasia.
The DNA methodology used was first the RFLP with restrition
enzymes and, if the mutation was not detected, we used direct sequencing
of all gene.
In Achondroplasia we detected 75 cases with the G1138A mutation, 2
cases with the G1138C mutation, 1 case with the G1123T and 1 case
with a C1150T mutation. When we studied the C1150T mutation in 50
normal Brazilians from different ethinic origins we detected 1 person
with this mutation, and concluded that this mutation is a polymorphism
.We didn’t detected the pathologic mutation in two typical achondroplasia
patients.
In Hypochondroplasia we found 14 patients with the C1620G mutation
and 7 cases with the C1620A mutation . We didn’t detected the mutation
in one typical hypochondroplasia patient.
In Thanatophoric Dysplasia we had 7 patients with the type I, all of
them presented the C742T mutation and, 2 cases of the type II, both
presented the A1948G mutation.
This is the first study of a brazilian patients sample for FGFR3 mutations
and we could concluded that the types and frequencies of FGFR3 mutations
detected are similar to that described in other regions studied.
We could define that the C1150T mutation ( Trujillo et al., 2004) and
detected by us in one achondroplasia patient is a polymorphic variant
not related to diseases determined by mutations in FGFR3 gene.
P0732. MEFV Mutations in Turkish Patients Suffering From
Familial Mediterranean Fever
M. Ozdemir 1 , O. Cilingir 1 , C. Korkmaz 2 , M. H. Muslumanoglu 1 , D. Uzun 1 , O.
Kutlay 1 , S. Artan 1 ;
1 Eskisehir Osmangazi Universty Medical Faculty Department of Medical Genetics,
Eskisehir, Turkey, 2 Eskisehir Osmangazi Universty Medical Faculty Department
of Rheumatology, Eskisehir, Turkey.
Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory
periodic disorder characterized by febrile and painful attacks
due to inflammation involving the serosal membranes in the abdomen,
chest or joints. Over 50 mutations have been identified in the
MEFV gene responsible for FMF. AIM: To identify the distribution and
the frequency of the MEFV gene mutations in Turkish FMF patients
PATIENTS AND METHODS: The study was carried out on 354 clinically
diagnosed Turkish FMF patients. Mutation screening of the MEFV
gene was performed by DNA sequencing of exon 10 in all patients
and by FMF specific StripAssay (this assay is based on a Polymerase
Chain Reaction-Reverse Hybridization technique) for E148Q, P369S
and F479L mutations of exons 2,3, and 5, respectively in 88 patients.
RESULTS: Of the 354 unrelated patients investigated, 179 (50.6%)
had one or two mutations : 38 patients (10.7%) were homozygous; 44
(12.4%) were compound-heterozygous; 97 (27.4%) heterozygote mutations.
Of the mutations, M694V (A>G), M680l (G>C), V726A, R761H
accounted for 73.7, 18.4, 5.3, and 2.6 %, respectively. The E148Q,
P369S and F479L mutations of exons 2, 3 and 5 were seen in one
case each. One case was E148Q/M680I compound-heterozygous.
CONCLUSION: Exon 10 is the most common site for FMF mutations
in Turkish population is exon 10 whereas exons 2,3 and 5 accounts
for about 4.5% of the cases. The commonest mutation among Turks
is M694V (A>G). Morever, because of confirmed results, StripAssay
for 12 common mutations might be used in routine mutation screening
analysis.
P0733. Identification of two new alternatively spliced MEFV
transcripts in human peripheral blood leukocytes
S. Grandemange1 , C. Notarnicola2 , I. Touitou1 ;
1 2 Institut de génétique humaine, Montpellier, France, INSERM, Montpellier,
France.
Familial Mediterranean fever (FMF) is an autosomal recessive disease
characterized by recurrent attacks of fever and serositis. FMF is
1