2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
mature aging, skin laxity and generalised osteoporosis with spontaneous
fractures . Craniofacial dysmorphism include a prominent forehead,
ptosis, large protruding ears, droopy cheeks, flat malar region
and prognathism .
We ascertained a Libanese family in which 3 individuals presented
with GO . The proband aged 1 ½ years is born from sixth-degree consanguineous
parents, while in his 2 maternal uncles (born from a maternal
uncle who married his second-degree cousin) the diagnosis was
posed at 21 and 18 years, respectively . A genome-wide search was
performed by genotyping the 3 affected individuals for microsatellite
markers spaced around 10-15 cM from the ABI PRISM® Linkage Mapping
Set seeking for adjacent homozygous markers . Among 6 positive
regions, haplotype reconstruction and genotyping of other family members
allowed the identification of a unique informative 47 centimorgan
region of homozygosity, shared only by the 3 patients . We generated 9
novel microsatellite markers in order to refine this region and outlined a
locus for GO spanning from 155 .15 to 174 .71 megabases on the long
arm of chromosome 1 (max Lod score 3 .2) . Sequencing of candidate
genes within the linked interval is still in progress .
P06.118
Large deletions in 9q22.21-9q22.33 region of Gorlin syndrome
patients
V. Musani 1 , P. Gorry 2 , A. Basta-Juzbašić 3 , S. Levanat 1 ;
1 Rudjer Boskovic Institute, Zagreb, Croatia, 2 Laboratoire de Génétique, Développement
& Cancer, Université V. Ségalen, Bordeaux, France, 3 Department
of Dermatovenerology, University School of Medicine, University of Zagreb,
Zagreb, Croatia.
Gorlin syndrome, also known as Nevoid Basal Cell Carcinoma Syndrome
(NBCCS) or Basal Cell Nevus Syndrome (BCNS), is an autosomal
dominant disorder that is characterized by various developmental
abnormalities, like cysts of the skin, jaw cysts, bone malformations and
different tumors like basal cell carcinomas (BCC) as most frequent,
and also medulloblastomas, meningiomas, fibromas of the ovaries and
heart . The prevalence is estimated at one per 57000 . Phenotypical
and genotypical diversity in Gorlin syndrome is referring to inactivating
mutations in only one gene, PTCH, the human homologue of the Drosophila
segment-polarity gene patched . PTCH is a tumor suppressor
gene, located at 9q22 .3, encoding a 12-pass transmembrane glycoprotein
that acts as an antagonist in the Hedgehog signaling pathway .
The 34 kb gene contains 23 exons and there are several hundred
mutations, spanning the whole gene . Although there are some recurring
mutations, there are no apparent hot spots . Nonsense, frameshift,
in-frame deletions, splicesite, and missense mutations all have been
described in the Gorlin syndrome patients . In some cases large deletions
in PTCH region have been reported . We developed semi-quantitative
fluorescent multiplex PCR with polymorphic markers surrounding
PTCH and analyzed the whole 9q22 region in 50 Gorlin syndrome
cases from France and Croatia . In three cases we found large deletions
from 4-7 megabases in length, giving some depth and additional
indications for phenotype diversity of the Gorlin syndrome .
P06.119
Analysis of CTLA Gene Polymorphisms in spanish
Graves`Patients
M. Piñeiro-Gallego 1 , P. Álvarez-Vázquez 2 , L. Constela 3 , R. García -Mayor 2 , D.
Valverde 1 ;
1 Departamento de Bioquímica, Genética e Inmunología., Vigo, Spain, 2 Complejo
Hospitalario Universitario de Vigo., Vigo, Spain, 3 Complejo Hospitalario
Universitario de Vigo, Vigo, Spain.
Graves’ disease (GD) is a common organ-specific autoimmune disease
that affects 0 .5%-1% of Western population . It is a multifactorial
disease that develops as the result of a complex interaction between
genetic susceptibility genes and environmental factors . GD is characterized
by diffuse goiter, ophthalmopathy, and anti-thyroid-stimulating
hormone receptor antibodies .
Numerous studies have demonstrated the linkage to several polymorphism
of the CTLA4 gene . The CTLA4 gene is placed on chromosome
2q33 and codifies the T cell receptor, which negatively modulates the
immune response disabling the T cells . The aim of the present work
was to determinate the contribution of C/T dimorphism in the promoter
at position -318, the A/G dimorphism at position + 49 in exon 1, and
the C/T60 dimorphism in the 3’UTR of the CTLA4 gene to the severity
and manifestations of GD .
A cohort of 98 patients, and 50 healthy controls were used to genotype
these three SNPs by PCR-RFLPs .
Results from +49A/G showed significant differences for the genotypes
between Graves’ patients and controls . The frequency of GG is higher
than in controls, a 6% of the controls were homozygous for the G allele,
while for the patients group we found 22%. Furthermore, significant
increase in the frequency of the G allele was found in Graves’
patients compared with controls (X²= 6 .04, P=0 .0140)
No statistically significant association has been found with the -318
A/G and CT60 3’UTR polymorphism (X² = 17 .8, P =0 .1815; X² = 0 .79,
P=0 .3729 respectively) .
P06.120
5 base pair deletions in Rab27a gene as hot spot in exon 6 in
Griscelli syndrome (type ii)
S. Shahkarami 1 , Z. Pourpak 2 , M. Houshmand 3 , A. Hamidieh 2 , M. Moin 2 ;
1 Immunology, Asthma and Allergy Institue (IAARI), Tehran, Islamic Republic
of Iran, 2 Immunology, Asthma and Allergy Institue (IAARI),, Tehran, Islamic
Republic of Iran, 3 National Institute of Genetic Engineering and Biotechnology,
and Medical Genetic Lab, Special Medical Center, Tehran, Iran, Tehran, Islamic
Republic of Iran.
Griscelli syndrome (GS), an autosomal recessive disorder, is characterized
by a silver-gray sheen of the hair and the presence of large
clusters of pigment in the hair shaft . GS can be associated to neurological
impairment (GS1), immunodeficiency (GS2), or be isolated
(GS3) .
GS2 is caused by a mutation in the small GTPase RAB A gene . The
aim of this study was to investigate mutations in RAB A gene, in a
3 year-old boy who was referred to our center with immunodeficiency
and silver gray sheen of the hair .
Material and method: Genomic DNA was extracted from peripheral
blood cells by salting out method. Five coding exons were amplified by
PCR-Sequencing methods and sequenced to detect probable mutations
in RAB A gene .
Result: A homozygote deletion was found in exon 6 of the RAB A
gene .
Discussion: This deletion leads to a frame shift mutation in exon 6 and
a premature stop codon. Clinical manifestations and immunodeficiency
help physician to suspect diagnosis of GS II . As molecular analysis
has provided an exact way to investigate mutations in immunodeficient
patients like GS, it can be considered as a very useful method for
definite diagnosis.
Because of an amino acid deletion and frame shift in this exon, we
conclude that this new deletion is pathogen . Other deletions were
found and reported in the same exon as causative mutation . We believe
that this region may be a hot spot for GS II and suggest that the
first analysis for other patients must be done in this region.
P06.121
Association study of the glycogen synthase kinase-3 beta
(GSK3beta) gene with Mood Disorders
M. Gratacòs 1 , V. Soria 2 , E. Saus 1 , F. Vivarelli 1 , J. R. González 3 , J. Valero 4 , È.
Martínez-Amorós 2 , M. Bayés 1 , A. Gutiérrez-Zotes 4 , J. M. Crespo 2,5 , L. Martorell 4 ,
E. Vilella 4 , A. Labad 4 , J. M. Menchón 2,5 , J. Vallejo 2,5 , X. Estivill 1,6 , M. Urretavizcaya
2,5 ;
1 CIBERESP (CIBER en Epidemiología y Salud Pública), Genes and Disease
Program and CeGen Barcelona Genotyping Node, Center for Genomic Regulation,
Barcelona, Catalonia, Spain, 2 Mood Disorders Clinical and Research Unit,
CIBER-SAM, Psychiatry Department, Bellvitge University Hospital, L’Hospitalet
de Llobregat, Barcelona, Catalonia, Spain, 3 CREAL, Center for Research in
Environmental Epidemiology, Barcelona, Catalonia, Spain, 4 Grup d’Investigació
en Psiquiatria. Hospital Universitari Institut Pere Mata, Rovira i Virgili University,
Reus, Tarragona, Catalonia, Spain, 5 Department of Clinical Sciences, Bellvitge
Campus, Barcelona University, Barcelona, Catalonia, Spain, 6 Experimental and
Health Sciences Department, Pompeu Fabra University, Barcelona, Catalonia,
Spain.
Glycogen synthase kinase-3beta (GSK3beta) is a key component of
the Wnt signaling pathway and is known to regulate such critical cellular
functions as structure, gene expression, mobility and apoptosis .
Recent findings support that GSK3beta may play a role in the pathophysiology
and treatment of Mood Disorders (MD) . We hypothesize
that genetic variants, including SNPs and CNVs (Copy Number Varia-