2009 Vienna - European Society of Human Genetics

Metabolic disorders
Normal Affected PND No of cases No of families Diagnosis
87
45
25
2
14
40
16
14
3
6
msP iii
MSP III A
MSP IIIB
MSP III C
MSP IIID
70 29 MPS II
52 28 MPS I
33 17 MPS VI
33 17 MPS IV
62 27 (33%) 89 278 134 total
Relative incidence of MPS cases &
Prenatal Diagnosis in affected Iranian families
P13.41
Functional analysis of the gene deficient in MPS IIIC patients
A. O. Fedele 1,2 , M. Filocamo 3 , M. Di Rocco 4 , G. Sersale 5 , T. Lübke 6 , P. Di Natale
7 , M. P. Cosma 2 , A. Ballabio 2 , J. J. Hopwood 1 ;
1 Lysosomal Disease Research Unit (LDRU), SA Pathology, North Adelaide,
Australia, 2 Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy,
3 Laboratorio Diagnosi Pre-Postnatale Malattie Metaboliche, Istituto G. Gaslini,
Genoa, Italy, 4 U.O. Pediatria II, Istituto G. Gaslini, Genoa, Italy, 5 Clinica Pediatria,
Università Milano Bicocca, Monza, Italy, 6 Institut für Biochemie 2, Göttingen,
Germany, 7 Department of Biochemistry and Medical Biotechnologies,
Federico II University, Naples, Italy.
Mucopolysaccharidosis (MPS) IIIC is an autosomal recessive lysosomal
storage disorder caused by a deficiency in heparan acetyl CoA:
alpha-glucosaminide N-acetyltransferase (HGSNAT). This is localised
to the lysosomal membrane and catalyses a transmembrane acetylation
in which the terminal glucosamine residue of heparan sulphate acquires
an acetyl group, thus forming N-acetylglucosamine. The characteristic
feature is the deterioration of the central nervous system,
but other symptoms may include coarse facies, developmental delay,
macrocrania and motor retardation. Only recently has the gene for
MPS IIIC been identified. HGSNAT is localised to chromosome 8p11.1
and contains 18 exons. The cDNA codes for a product of 635 amino
acids which is predicted to contain a cleavable signal peptide at its
N-terminus, 11 transmembrane domains, and up to 5 N-linked glycosylation
sites. We and other groups have since sequenced 45 different
disease-causing HGSNAT alleles in MPS IIIC patients. 19 of these are
missense mutations, although these are yet to be functionally analysed.
Furthermore, certain biochemical properties of HGSNAT, such
as its active site, remain uncharacterised. In this study, a number of
mutations known to occur in MPS IIIC patients have been introduced
into the cDNA of HGSNAT. The expression of these HGSNAT derivatives
in cell culture and the analysis of their protein levels and activity
have been performed to examine the effect of the tested mutations on
HGSNAT function. This research will aid in detailing the biochemical
characteristics of HGSNAT activity, and thus the molecular basis of
MPS IIIC.
P13.42
GBA gene variants are associated with PD in France
M. Anheim 1 , C. Condroyer 2 , S. Lesage 2 , A. Troiano 3 , A. Durr 4 , A. Brice 5 ;
1 Genetics Department, Pitié Salpêtrière Hospital, Paris, France, 2 INSERM,
UMRS975, UPMC Univ Paris 06, CRicm, Paris, France, 3 Genetics Department,
INSERM, UMRS975, Pitié Salpêtrière Hospital, Paris, France, 4 Genetics Department,
INSERM, UMRS975, UPMC Univ Paris 06, CRicm, Pitié Salpêtrière
Hospital, Paris, France, 5 Genetics Department, INSERM, UMRS975, UPMC
Univ Paris 06, CRicm, Federation of the Nervous System Diseases, Pitié
Salpêtrière Hospital, Paris, France.
Objective :
To compare the frequency of variants in the GBA gene which encodes
β-glucocerebrosidase, in Parkinson’s disease (PD) patients and in
controls. To compare the clinical features of GBA-PD patients with PD
patients without any mutations.
Background :
Homozygous mutations of GBA are responsible for Gaucher disease.
It has been reported that heterozygous mutations of GBA was a risk
factor for PD, especially in Ashkenazi Jews.
Methods :
GBA sequencing was performed in 293 mostly (87%) French PD pa-
tients and 252 age-matched controls.
Results :
Mean age at examination was 57.7±11.5 years (33-85) for PD and
57.8±11.9 (31-85) for controls. Mean age at onset and mean disease
duration were 47.5±10.0 years (30-70) and 10.3±6.6 (1-30). GBA variants
were more frequent in PD compared to controls (11% versus 0.4%,
p