2008 Barcelona - European Society of Human Genetics

Clinical genetics
mutations, all of them previously described in the literature: two juvenile
patients, one of which was homozygous for p .R505Q and the other
compound heterozygous for c .1509-26G>A; ,and four infantile patients
homozygous for p .P417L, p .Y266D, c .782_785delCTTT and c .1305_
1306delAG, respectively. Overall our findings point out to 3 particularly
interesting aspects of the mutational spectrum of the Spanish population:
Null frequency of the common 16 Kb deletion at 5’ of the gene, an
outstanding degree of homozygosity ( 72% of patients) and a remarkable
prevalence of an allele carrying a deletion of a single nucleotide
(c .171delG) which accounts for 27% of total mutant alleles .
P01.069
mutation analysis in spanish and moroccan Patients with
Mucopolysaccharidosis IIIC (Sanfilippo C Syndrome)
I. Canals 1,2,3 , M. J. Coll 4,3 , A. Chabás 4,3 , D. Grinberg 1,2,3 , L. Vilageliu 1,2,3 ;
1 Universitat de Barcelona, Barcelona, Spain, 2 IBUB, Barcelona, Spain, 3 CI-
BERER, Barcelona, Spain, 4 Institut de Bioquímica Clínica, Hospital Clínic,
Barcelona, Spain.
Mucopolysaccharidosis (MPS) describes any inherited lysosomal storage
disorder resulting from inability to catabolize glycosaminoglycans .
MPS III, or Sanfilippo Syndrome, is the type of MPS that results from
a deficient heparan sulfate degradation and presents an autosomal
recessive inheritance . Clinical symptoms are similar for all types of
MPS III and they are due to the lysosomal storage of heparan sulfate .
The most important feature is the progressive and severe deterioration
of the central nervous system during childhood .
HGSNAT is the gene responsible for MPS IIIC that has been recently
identified. It encodes the acetyl CoA:α-glucosaminide N-acetyltransferase,
which is a lysosomal membrane protein required to N-acetylate
the terminal glucosamine residues of heparan sulfate . To date, about
fourty mutations have been described in MPS IIIC patients .
In this study we have identified the mutant alleles in five Spanish and
one Moroccan patients . A total of six different alleles have been found
in this mutational analysis, five of which are novel. One of these alleles
contains a double mutation (c .318+1G>A, p .P265Q) previously
described, three alleles bear splice-site mutations (c .456-2A>G,
c .717+1G>A and c .1462-1G>A) and the other two contain missense
mutations (p .G452V and p .L473P) . Furthermore, two new possible
single nucleotide polymorphisms (SNP) have been identified in intron
1 and intron 5, respectively . Samples from three new patients, one
Spanish and two Moroccan, have recently arrived and are currently
being analyzed .
This work is being carried out in collaboration with the MPS España.
The financial support from this association is acknowledged.
P01.070
Novel mutation in tay-sachs (HEXA gene)
M. Rostami 1 , M. Dehghan Manshadi 1 , T. majidizadeh 1 , M. Nateghi 2 , M. Houshmand
1 ;
1 National Institute Center Genetics Engineering & Biotechnology, Tehran, Islamic
Republic of Iran, 2 Special Medical Center, Tehran, Islamic Republic of Iran.
Tay-Sachs disease is a fatal genetic autosomal recessive disorder,
most commonly occurring in children, those results in progressive
destruction of the nervous system . Tay-Sachs is caused by the absence
of a vital enzyme called hexosaminidase-A (Hex-A) . Tay-Sachs
disease, the prototype hexosaminidase A deficiency, is characterized
by progressive weakness, loss of motor skills, decreased attentiveness,
and increased startle response beginning between three and
six months of age with progressive evidence of neurodegeneration,
including seizures, blindness, spasticity, eventual total incapacitation,
and death, usually before age four years . The infant gradually regresses,
and is eventually unable to crawl, turn over, sit or reach out .
The HEXA gene provides instructions for making one part of enzyme
called (beta-hexosaminidase A). Specifically, the HEXA gene carries
instructions for the alpha subunit of this enzyme . One alpha subunit
joins with one beta subunit (produced from the HEXB gene) to form
a functioning enzyme. Mutations in the gene coding for the β subunit
lead to a deficiency of both the HEX A and HEX B form of the enzyme
.More than 100 mutations that cause Tay-Sachs disease have been
identified in the HEXA gene. The HexA gene is located on the human
15q23-q24 chromosome .
In present study DNA was received from a consanguineous couple
who had 1 affected child from who no sample was available . For each
sample we performed genetic analysis of HEXA gene by direct sequence
analysis . It was found heterozygote delG mutation in exon 14
of HEXA (β subunit).
P01.071
mutations in the urocanase gene UROC cause urocanic
aciduria
C. Espinós 1 , M. Pineda 2 , D. Martínez-Rubio 1 , A. Ormazabal 2 , M. A. Vilaseca 2 ,
L. J. M. Spaapen 3 , F. Palau 1 , R. Artuch 2 ;
1 Instituto de Biomedicina de Valencia, CSIC and Centro de Investigación Biomédica
En Red de Enfermedades Raras (CIBERER), Valencia, Spain, 2 Hospital
Sant Joan de Déu and Centro de Investigación Biomédica En Red de Enfermedades
Raras (CIBERER), Barcelona, Spain, 3 University Hospital Maastricht,
Maastricht, The Netherlands.
The urocanase deficiency (MIM 276880) is a rare disease with only
two reported cases, due to the abnormal activity of the urocanase enzyme
(histidine pathway) that catalyzes the transformation from urocanic
acid to formininoglutamate (FIGLU) . The biochemical hallmark
is the urocanic aciduria . We have investigated the urocanase gene
UROC1 gene in a girl presenting ataxia with mental retardation (IQ
= 54) and extremely high levels of urocanic acid in urine, ranging between
158-202 mmol/mol creatinine (normal values below 10 mmol/
mol creatinine) . The genetic analysis of the UROC1 gene revealed that
the propositus is a compound heterozygote for the mutations p .L70P
(c .209T>C) and p .R450C (c .1348C>T) . Her healthy father was heterozygous
carrier of the p .R450C mutation . In silico analysis showed that
the L70 residue could form part of an α-helix, and then the change to
proline may disrupt the α-helix, possibly resulting in an alteration of
the structure of the N-terminal region . The R450 residue forms a saltbridge
with the urocanate, substrate of the urocanase . Presence of an
arginine residue as the consequence of the mutation would interrupt
the urocanase interaction with urocanate . Consequently, the in silico
predictions suggest that both mutations in the UROC1 gene, p .L70P
and p.R450C, are pathologic. We suggest that urocanase deficiency
or urocanic aciduria is a Mendelian disorder of the histidine metabolism
caused by mutations in the UROC1 gene . The toxic effect of the
urocanic acid and also, the possible folate deficiency would play a notable
role in the physiopathology of this rare condition .
P01.072
mutation screening in genes coding for AtP7A, AtP7B and
AtOX1 in czech patients with menkes disease and Wilson
disease
L. Pospisilova 1 , L. Kralik 1 , R. Bruha 2 , Z. Marecek 2 , E. Flachsova 1 , P. Fruhauf 3 ,
A. Kral 1 , J. Zeman 1 , P. Martasek 1 ;
1 Department of Pediatrics,1st School of Medicine, Charles University Prague,
Prague 2, Czech Republic, 2 Department of Internal Medicine 4,1st School of
Medicine, Charles University Prague, Prague 2, Czech Republic, 3 Faculty General
Hospital Prague, Department of Pediatrics, Prague 2, Czech Republic.
Copper plays an essential role as a cofactor for many enzymes . There
are two intracellular copper transferring P-ATPases in human: ATP7A
and ATP7B, and a chaperone ATOX1 which delivers copper to them .
Deficiency of ATP7A causes X-linked Menkes disease (MD). A defect in
ATP7B causes autosomally recessive inherited Wilson disease (WD) .
Here we report the mutational analysis of the ATP7A and ATP7B genes
of 4 patients with MD and 130 patients with WD from the Czech Republic
.
Genomic DNA was used to amplify 23 exons of the ATP7A gene and
21 exons of the ATP7B gene . PCR products were examined by RFLP
and sequenced . We introduced fast mutation screening based on
differences in melting temperature of DNA fragments with sequence
variations . We performed mutation analysis of the ATOX1 gene in patients
whose clinical and biochemical phenotypes suggest impaired
copper transport, but no mutations were found within the ATP7A and
ATP7B genes .
Molecular analysis revealed 4 mutations in the ATP7A gene, two of
which have not been previously published (Q724X and E1249X) . 14
mutations were found in the ATP7B gene (including prevalent H1069Q
mutation, and the newly found A1135T mutation), and no mutations in
ATOX1 gene .
Molecular analysis of the ATP7A gene allows for genetic counselling in
families affected by MD . Screening for the prevalent H1069Q mutation
in the ATP7B gene shows that the frequency- 38 .8% of analysed al-