2009 Vienna - European Society of Human Genetics

Molecular basis of Mendelian disorders
$ cDNA sequence reference AY055384
* normal range : 28-244 ng/ml (unpublished data, Ganz et al)
§ current values for patients under iron therapy (oral or IV) excepted for patient 7, indicated by #. Hb of patient 7 reached 11.5 in 2001
after IV iron therapy.
¤ patient also heterozygote for the p.R446W
£ donor splice site of intron 11 is predicted to be suppressed
abreviations : IRIDA : iron-refractory iron deficiency anemia, LDLRA :low density lipoprotein receptor class A domain, CUB : complement
factor C1r/C1s, urchin embryonic growth factor and bone morphogenetic protein, SEA : sea urchin sperm protein, enteropeptidase,agrin,
SP: serine protease, y year, m month
P12.099
The first report of IVSI-II(T>C) from Iran in three β-Thalassemia
carrier
Z. Kaini Moghaddam, M. Karimipour, M. Taghavi, E. Shafieyeh, M. Mohammadi,
M. Jafarinejad, S. Fathiazar, S. Zeinali;
Pasteur Institute of Iran, Tehran, Islamic Republic of Iran.
β-Thalassemia is the most frequent single gene disorder in Iran.The
cause of the disease is defect in the synthesis of β- globin chain and
has been reported from different parts of the world . Ordinairly, in any
population there are specific mutations. The type of β-thalassemia mutation
has influence on the β- globin chain synthesis represented by β 0
, β + and β ++ thalassemia. β -Thalassemia is very prevalent in northen
proviences of Iran and the most regional a common mutation is IV-
SII-I(G>A). Some of the β-Thalassemia carriers reffered to our clinic
for mutation detection remained uncharacterized after ARMS analysis
for known mutations. Among These individuals, three carriers were
identified by direct sequencing of the PCR-amplified product, which
had T>C substituation HBB.C.92+2 T>C (IVSI-II). Here we report a
mutation in β-globin gene found in three individual carriers of β-Thalassemia
referred to our lab.After obtaining written informed consent,
genomic DNA was extracted from peripheral leukocytes by salting out
method. ARMS-PCR was exploited for detecting common mutations
and DNA sequencing was performed for finding unknown mutations in
β-globin gene.Among carreiers of β -Thalassemia referred to us three
had the above mutation.To our best knowledge this is the first report of
this mutation from Iran.The indices (MCV and MCH) and HbA 2 of these
carriers were like reports in globin gene server.
P12.100
mutations spectrum of juvenile polyposis syndrome in Poland
M. Podralska 1 , W. Cichy 2 , M. Teisseyre 3 , J. Steffen 4 , D. Nowakowska 5 , E. Czkwanianc
6 , M. Skrzypczak 1 , R. Slomski 1 , A. Plawski 7 ;
1 Institute of Human Genetics, Poznan, Poland, 2 University of Medical Sciences,
Poznan, Poland, 3 Children’s Memorial Health Institute, Warszawa, Poland,
4 Institute of Oncology, Warszawa, Poland, 5 Institute of Oncology, Poznan, Poland,
6 Institute of Polish Mother’s Memorial Hospital, Lodz, Poland, 7 Instytitute
of Human Genetics, Poznan, Poland.
Juvenile polyposis (JP) is a genetically determined predisposition to
occurrence of multiple juvenile polyps in gastrointestinal tract and associated
malformations such as: porphyria, psoriasis, mental retardation,
congenital heart disease, cleft lip and palate, epilepsy, hereditary
haemorrhagic telangiectasia, digital clubbing in children. Hypertrophic
pulmonary osteoarthropathy and malrotation of the gut also could be
observed. Prevalence of JP syndrome is 1 per 100000. The JP syndrome
is inherited in an autosomal dominant manner and the risk of
malignancy in JPS patient is increased and could be ranged more then
60% in alimentary tract. We performed mutation analysis in DNA isolated
from 17 Polish patients with JPS. The entire coding sequence
of the BMPR1A and SMAD4 genes were studied. We used methods
SSCP and HA analysis for mutation screening. The DNA fragment
presenting different migration patterns on the polyacrylamide gels
were sequenced by direct PCR product sequencing using automated
DNA sequencer according to manufacturer’s instruction. In result of
molecular investigations we observed five mutations and ten exonic
polymorphism and intronic variations. Moreover, using the Multiplex
Ligation-dependent Probe Amplification (MLPA) - method with kit
P158-A1 (MCR Holland) we were able to detected five additional large
mutations. Detected the genomic deletions have size ranging from one
exon to two whole genes. In our study in one case we observed deletion
both PTEN and BMPR1A genes.
The study was supported by the Polish Ministry of Science and Higher
Education projects no. 2PO5E02630 and N401 014435
P12.101
Karak syndrome in two saudi Arabian families with linkage to
PLA2G6 locus
H. Azzedine 1 , M. A. M. Salih 2 , E. Mundwiller 1 , A. Khan 3 , A. Aldriss 4 , E. A. Elmalik
5 , M. M. Kabiraj 6 , G. Stevanin 1 ;
1 INSERM/UPMC UMRS 975 (exU679), Paris, France, 2 Division of Pediatric
Neurology, College of Medicine, King Saud University, Riyadh, Saudi Arabia,
3 King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia, 4 Division of Pediatric
Neurology, College of Medicine, King Saud University, Riyadh, Saudi Arabia,
5 Department of Physiology, College of Medicine, King Saud University, Riyadh,
Saudi Arabia, 6 Division of Clinical Neurophysiology, Department of Neuroscience,
Armed Forces Hospital, Riyadh, Saudi Arabia.
A hetererogeneous group of severe neurological disorders like Aceruloplasminaemia,
Neuroferritinopathy, Hallervorden-Spatz syndrome,
HARP syndrome, and Fridreich ataxia involve excess brain iron accumulation.
The “eye of the tiger” sign is a common neuroradiological
finding in neurodegeneration with iron brain accumulation type 1
and 2 (NBIA1, 2), infantile neuroaxonal dystrophy (INAD) and Karak
syndrome (KS). Mutations in PANK2 and PLA2G6 genes were implicated
in NBIA, INAD and KS disorders. We describe 2 consanguineous
Saudi families with Karak syndrome. These consisted of 4 affected
individuals (1 male and 3 females, aged 5 - 24 years). Onset ranged
between 1 and 7 years with progressive cerebellar ataxia and spasticity
associated, later, with extrapyramidal signs, intellectual decline and
axonal form of Charcot-Marie- Tooth disease (CMT2). Ambulation was
lost between 4 1/2 and15 years. One male patient died at 24 years.
Ophthalmic evaluations revealed abnormal vertical saccades and pursuit.
Brain MRI showed iron deposition in the putamen in all patients.
These 2 families were genotyped for PANK2 and PLA2G6 loci using
10 microsatellite markers. PANK2 locus was excluded while assignment
of the families to the PLA2G6 locus was established by homozygocity
mapping. Direct sequencing of the PLA2G6 gene is in progress
as well as the genotyping of 3 other consanguineous families with the
same phenotype and belonging to same country. The results of these
investigations will be shown during the meeting.
P12.102
molecular genetic analysis of families with Keratosis Follicularis
Spinularis Decalvans in a refined KFSD locus
E. Aten 1 , R. H. A. M. Vossen 1 , I. B. Hooijkaas 1 , M. J. R. van der Wielen 1 , E.
Bakker 1 , J. C. Oosterwijk 2 , M. H. Breuning 1 , J. T. Den Dunnen 1 ;
1 Center of Human and Clinical Genetics, Leiden University Medical Center,
Leiden, The Netherlands, 2 Department of Clinical Genetics, University Medical
Center Groningen, Groningen, The Netherlands.
KFSD (Keratosis Follicularis Spinularis Decalvans, OMIM 308800) is
a rare genetic disorder affecting both skin and eyes. It is characterized
by follicular hyperkeratosis of the skin developing into patchy scarring
alopecia and loss of the follicles of the hair, eyelashes, and eyebrows.
Associated eye symptoms include photophobia in childhood and/or
blepharitis and corneal dystrophy. Due to the clinical heterogeneity
of KFSD the definitive diagnosis is often challenging. KFSD closely
resembles other disorders where abnormal keratinization is involved
such as keratosis pilaris atrophicans faciei (KPAF), atrophoderma vermiculatum
(AV) and ichtyosis follicularis with atrichia and photophobia
(IFAP). The question remains whether these syndromes are simply
variations of the same entity or truly independent.
Although an X-linked pattern of inheritance has been confirmed in two
different families, the existence of a rare autosomal dominant variant
has been postulated. Linkage and recombination analysis in a large
Dutch family identified two key recombinants mapping the KFSD locus
to Xp22.11-p22.13. Towards identification of the causative gene, we
studied the large Dutch family and together with some other families
with a clinical diagnosis of KFSD using new molecular tools. 1M SNP
arrays were used to refine the locus to a 2.9 Mb region and to exclude
the involvement of large deletions and duplications. At present,
the 14 genes in the candidate gene interval are screened for possible
pathogenic variants. Finally, whole genome gene expression profiling
is currently used to study differences between patient and control fibroblasts.