2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
been analyzed by DHPLC in a cohort of 37 boys presenting a hypomyelination
without mutation in the PLP1 gene . A MCT8 mutation has
been identified in 4 patients from 4 independent families. These results
demonstrate the interest of MCT8 mutation screening in hypomyelinating
leukodystrophies of unknown origin and suggest, at least in humans,
a new role of MCT8 in oligodendrocyte maturation .
P05.200
Alopecia areata: Association with resistance to thyroid
hormones
R. Bircan 1 , T. Güran 2 , T. Akcay 2 , S. Turan 2 , A. Bereket 2 ;
1 Namik Kemal University, Faculty of Arts and Sciences, Department of Molecular
Biology and Genetics, Tekirdag, Turkey, 2 Marmara University, School of
Medicine, Dept. of Pediatric Endocrinology, Istanbul, Turkey.
Context : Resistance to thyroid hormone (RTH) syndrome is a rare
genetic disorder, generally characterized by the absence of the usual
symptoms and metabolic consequences of thyroid hormone excess .
Mostly it is caused by thyroid hormone β receptor mutations. Up to
date 124 mutations in the TRβ gene identified in 500 different families.
Besides, alopecia areata (AA) is an autoimmune disease of the hair
follicle, frequently associated with other autoimmune disorders, one
of the most common of which are thyroid diseases like hashimoto thyroiditis
and Graves’ disease .
Objective: we described a family having RTH syndrome, caused by a
novel TRβ mutation, coexisted with diffuse, patchy alopecia without
autoimmune thyroid disease in affected members
Design: For the precise diagnosis of RTH, genetic testing was carried
out on the index patient, two siblings, his mother and father . Genomic
DNAs were extracted from peripheral blood samples by using
standard protocols. Exon 7-10 of the thyroid receptor beta (TRβ) were
amplified by PCR and possible candidate mutations screened by using
direct DNA sequencing .
Main Outcome: A novel TRβ mutation (I353V) was found in a 9 1/3
years old boy having both RTH syndrome and alopecia areata . This
mutation was also detected in his father and elder brother who were
affected by RTH and also have alopecia areata . It could be Speculated
that alopecia areata might be a novel sign of RTH either coexisted with
the other distinctive clinical and phenothypical characteristics of the
syndrome .
P05.201
Functional characterisation of single nucleotide polymorphisms
in the coding region of the human tryptophan hydroxylase gene
TPH
K. Bokelmann, M. V. Tzvetkov, M. Sedej, J. Brockmöller;
University Medicine, Göttingen, Germany.
The tryptophan hydroxylase isoenzyme 2 (TPH2) catalyzes the ratelimiting
step of serotonin synthesis in the human brain . Reduced serotonin
synthesis may be linked with neuropsychiatric disorders like major
depression or bipolar disorder or with the success or failure in therapy
of these diseases . Several genetic variants in the coding region of
the TPH2 gene have been reported but, thus far, only few of them have
been functionally characterized . Here we present functional analysis of
the THP2 variants L36Q, P206S, P312P, A328V and D479E .
The enzyme variants were heterologously expressed in PC12 and
HEK293 cells . Enzyme activity of the protein variants was assessed as
amount of intracellular serotonin or 5-hydroxy-tryptophan measured by
HPLC . The expression rates were controlled by qRT-PCR and Western
blot .
The 328V variant showed significantly decreased activity both in PC-
12 (only 28% of the wild type activity, P