Mutation and haplotype analyses in 26 Spanish Sanfilippo syndrome type A patients: Possible single origin for 1091delC mutation

Abstract

Mucopolysaccharidosis IIIA, also known as Sanfilippo syndrome type A, is an autosomal recessive storage disorder caused by deficiency of sulfamidase. The disease results in severe central nervous system degeneration often with mild somatic features that may delay the clinical diagnosis. Molecular analyses would allow early and unequivocal heterozygote detection, providing a useful tool for genetic counselling. About 40 mutations have been reported in the sulfamidase gene, with a very uneven distribution in different patient populations. We have previously described the high prevalence of mutation 1091delC in a small number of Spanish Sanfilippo A patients. The aim of the present work is to extend the mutational study to a total of 26 unrelated patients and perform haplotype analysis in order to study the origin of some mutations. The whole coding region of the gene was scanned by SSCP analysis and sequencing. This allowed the identification of 14 different mutations, corresponding to 90% of the mutant alleles. Seven of these mutations were only found in this Spanish group of patients, three of which, R150W, R433Q and R433W, are described here for the first time. We have also analyzed four internal polymorphisms and constructed the corresponding haplotypes. Chromosomes bearing mutation 1091delC show a conserved haplotype suggesting a common origin for this mutation. Moreover, all other mutations found twice or more also have conserved haplotypes for those polymorphic markers.

Mucopolysaccharidosis type IIIA: Clinical spectrum and genotype‐phenotype correlations

“…The primers were designed using standard software (Primer3, http://frodo.wi.mit.edu/cgi-bin/primer3/ primer3_www.cgi). All coding exons (1)(2)(3)(4)(5)(6)(7)(8) and exon/intron boundaries of the SGSH gene were sequenced. PCR products were purified with using ExoSap-it (USB, Cleveland, OH).…”

“…4 Until now, 77 different mutations in the SGSH gene have been reported, including 56 missense mutations, 4 nonsense mutations, 1 splice site mutation, 9 small deletions, and 7 small insertions. [5][6][7][8] The rate of progression of central nervous system (CNS) disease in patients with MPS IIIA appears to be remarkably variable and is at least in part related to the genotype. The p.G122R, p.R206P, p.S298P, p.I322S, and p.E369K mutations in the SGSH gene are considered to produce a more attenuated Sanfilippo phenotype.…”

“…Until now, 77 different mutations in the SGSH gene have been reported, including 56 missense mutations, 4 nonsense mutations, 1 splice site mutation, 9 small deletions, and 7 small insertions 5–8…”

A novel mutation of SGSH and clinical features analysis of mucopolysaccharidosis type IIIA

“…Compound heterozygous missense mutations at nucleotide position c.1298 (c.1298G > A) and c.630 (c.630G > T) were identified in the proband, which could induce amino acid changes from Arg to Gln (p.Arg433Gln) and Trp to Cys (p.Trp210Cys), respectively (Table 1). According to OMIM, the c.1298G > A mutation was reported to cause Sanfilippo syndrome previously [7] (Fig. 3 A), and the c.630 G > T mutation has not been reported yet (Fig.…”

Mucopolysaccharidosis 3

“…Failure to degrade heparan sulfate may result from deficiency of one of the following four lysosomal enzymes (Bodamer et al 2014): 1. MPS IIIA caused by deficient heparan Nsulfatase (sulfamidase) (Karpova et al 1996;Blanch et al 1997;Bunge et al 1997;Chabas et al 2001) 2. MPS IIIB caused by deficient α-Nacetylglucosaminidase (Beesley et al 1998(Beesley et al , 2005Bunge et al 1999) 3.…”