2009 Vienna - European Society of Human Genetics

Metabolic disorders
tissues. BN-PAGE from liver and muscle biopsies was performed, followed
by in gel activity assays.
Results: Sequence analysis of POLG1 gene revealed compound heterozygosity
for the most commonly found mutation p.A467T in exon 7
and a novel splice-site mutation c.1251-2A>T in intron 6 resulting in an
in frame skipping of Exon 7. The liver biopsy showed marked deficiency
of Complex I, III and IV. In muscle we found an isolated Complex
IV deficiency, whereas in fibroblasts all activities were normal. There
was a 90% mtDNA depletion in liver, no depletion in muscle and a 30
% depletion in fibroblasts. In liver there was a reduced in gel activity
for complex I, no activity for complex IV, the activities of complex II
were equal to the control. In muscle we found decreased activity of
complexes I and II and no activity for complex IV.
Conclusion: This new splice site mutation affects a highly conserved
region of the protein and leads in combination with p.A467T to different
depletion levels in different tissues. It extends the number of POLG1
mutations associated with fatal childhood hepatoencephalopathy.
P13.45
Novel SUCLG mutations in a patient with encephalomyopathic
phenotype associated with mild methylmalonic aciduria and
mtDNA depletion
C. Rouzier 1 , K. Fragaki 1 , C. Caruba 2 , S. Desmet 3 , S. Tuffery-Giraud 4 , S. Le-
Guédard-Méreuze 4 , V. Paquis-Flucklinger 1,5 ;
1 Service de Génétique Médicale, Centre de référence des pathologies mitochondriales,
CHU, Nice, France, 2 Service de Biochimie, CHU, Nice, France,
3 Service de Réanimation Pédiatrique, CHU, Nice, France, 4 Laboratoire de génétique
moléculaire, Inserm U827, Institut Universitaire de Recherche Clinique,
Montpellier, France, 5 FRE CNRS 3086, Faculté de Médecine, Nice, France.
The mitochondrial DNA depletion syndromes (MDS) are a heterogeneous
group of severe mitochondrial disorders inherited as autosomal
recessive traits. Three main clinical forms have been described:
myopathic, encephalomyopathic and hepatocerebral. Recently, the
SUCLA2 and SUCLG1 genes, which code for different subunits of
succinate-CoA ligase, have been involved in patients with severe encephalomyopathy
and mild methylmalonic aciduria. However to date,
only one family with SUCLG1 mutation has been reported.
Herein, we report the clinical and molecular findings in a child with encephalomyopathic
MDS secondary to novel SUCLG1 mutations.
At birth, this child presented with a severe hypotonia, respiratory failure
and hypoglycemia. Metabolic investigations revealed lactic acidosis
and mild methylmalonic aciduria. Histologic, biochemical and molecular
analyses of the muscle showed respectively cox-negative fibers,
combined respiratory-chain enzyme deficiency and mtDNA depletion.
We identified two novel mutations in SUCLG1. One allele, inherited
from the mother, carried a missense mutation that changes a highly
conserved C to G (c.509C>G, p.Pro170Arg). Amino acid conservation,
in silico predictions and absence of this variant in 160 controls
are strong arguments for its pathogenicity. The second allele, inherited
from the father, carried a G to C substitution (c.97+3G>C) in intron 1. In
silico studies predicted this variant to affect splicing. Functional analyses
using reporter minigenes are in progress to ascertain the splicing
outcome of this intronic variation.
We described the clinical evolution of a child with MDS due to SU-
CLG1 mutations confirming its role in encephalomyopathic MDS with
mild methylmalonic aciduria.
P13.46
TCF L polymorphism is an independent risk factor for New
Onset Diabetes mellitus After transplantation: a cohort study on
1229 renal transplant patients.
M. J. Abramowicz1 , L. Ghisdal1 , C. Baron2 , Y. Lebranchu2 , Y. Le Meur3 , J. Rerolle3
, A. Lionet4 , F. Glowacki4 , K. M. Wissing1 , D. Abramowicz1 ;
1 2 3 ULB-Erasme Hospital, Brussels, Belgium, CHU Tours, Tours, France, CHU
Limoges, Limoges, France, 4CHRU Lille, Lille, France.
Objective: Whether New Onset Diabetes Mellitus After Transplantation
(NODAT) shares the same susceptibility genes with type 2 diabetes
mellitus has not been adequately assessed to date. The aim of our
study was to investigate the association between 11 type 2 diabetes
mellitus-associated polymorphisms and the risk of NODAT within the
first 6 months after-renal transplantation.
Methods: A total of 1229 patients free of diabetes at transplantation
were genotyped for 11 polymorphisms: rs7903146 (TCF7L2),
rs8050136 (FTO), rs7754840 (CDKAL1), rs5215 (KCNJ11),
rs1801282 (PPARG), rs1111875 (HHEX-IDE), rs13266634 (SLC30A8),
rs10811661 (CDKN2A-CDKN2B), rs4402960 (IGF2BP2), rs757210
(HNF1B), rs10010131 (WFS1). NODAT was defined by fasting plasma
glucose 126 mg/dL on at least two occasions or de novo hypoglycaemic
therapy.
Results: Patients who developed NODAT (N=145, incidence=11.8%)
within the first 6-months post-transplantation were compared to patients
free of NODAT (N=1084) for clinical and genetic factors. NO-
DAT was significantly associated with the following characteristics by
multivariate analysis: TCF7L2 polymorphism (P=0.014), older age
(P