IJUP08 - Universidade do Porto

Molecular characterization of the Portuguese patients with
Mucopolysaccharidosis IIIC: two novel mutations in the HGSNAT
gene
Coutinho MF 1,2 , Lacerda L 2 , Prata MJ 1,3 , Ribeiro H 2 , Lopes L 2 , Ferreira C 2 and Alves
S 2
1 Department of Zoology & Anthropology, Faculty of Sciences, University of Porto, Portugal.
2 Centro de Genética Médica Jacinto Magalhães, INSA I.P., Porto, Portugal.
3 IPATIMUP, Porto, Portugal
Mucopolysaccharidosis IIIC (Sanfilippo Syndrome C), is a lysosomal storage disorder
caused by the inherited deficiency of the lysosomal membrane enzyme acetyl–coenzyme
A: α-glucosaminide N-acetyltransferase (N-acetyltransferase), which leads to impaired
degradation of heparan sulfate. The gene that encodes this enzyme -HGSNAT- has been
recently identified [1,2].
Here we report on the molecular analysis of the HGSNAT gene in the 3 Portuguese patients
diagnosed with MPS IIIC that lead to the identification of two novel mutations: an
insertion c.525-526InsT and a splicing mutation IVS3-2A→G, which is responsible for the
skipping of exon 4.
Both mutations give origin to transcripts that lead to the synthesis of truncated nonfunctional
proteins. However, since the STOP codons appear very prematurely, these
transcripts are probably degraded by nonsense mediated mRNA decay.
Furthermore, having detected that c.525-526InsT accounts for 83% of the mutant alleles in
our patient series might be of great epidemiological relevance. Since there is no known
consanguinity among the patients here studied, c.525-526InsT can represent a founder
mutation in the context of the Portuguese population and consequently it must be
considered as a primary target in molecular studies of MPS IIIC in Portugal.
The strategies developed for mutation analysis, in this study, constitute valuable tools that
will allow carrier detection and prenatal molecular diagnostics, leading to the improvement
of genetic counselling with great benefits for the Sanfilippo C families.
References:
[1] Fan, Xiaolian, Zhang H, Zhang S, Bagshaw RD, Tropak MB, Callahan JW, Mahuran DJ.
(2006) Identification of the Gene Encoding the Enzime Deficient in Mucopolysaccharidosis IIIC
(Sanfilippo Disease Type C) The Journal of Human Genetics 2006 October; 79: 738-744.
[2] Hřebíček M., Mrázová L, Seyrantepe V, Durand S, Roslin NM, Nosková L, Hartmannová H,
Ivánek R, Cízkova A, Poupetová H, Sikora J, Urinovská J, Stranecký V, Zeman J, Lepage P,
Roquis D, Verner A, Ausseil J, Beesley CE, Maire I, Poorthuis BJ, van de Kamp J, van Diggelen
OP, Wevers RA, Hudson TJ, Fujiwara TM, Majewski J, Morgan K, Kmoch S, Pshezhetsky AV
(2006), Mutations in TMEM76 that cause Mucopolysaccharidosis IIIC (Sanfilippo C Syndrome)
The American Journal of Human Genetics 2006 November; 79L, 807-819.
143