Genetic studies in a cluster of Mucopolysaccharidosis Type VI patients in Northeast Brazil

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Abstract

Mucopolysaccharidosis type VI (MPS VI, Maroteaux–Lamy syndrome) is a lysosomal storage disease caused by deficiency of arylsulphatase B. The incidence of MPS VI is very low, usually less than 1 case for every 1,000,000 newborns. In Northeast Brazil we identified in the county of Monte Santo (52,360 inhabitants) thirteen patients with MPS VI. The aim of this work was to identify the mutation(s) present in these patients and analyze intragenic SNPs to define possible haplotypes. The 13 MPS VI patients were found to be homozygous for the p.H178L mutation. All patients have the same haplotype for the intragenic SNPs. Based on current data, the prevalence of MPS VI in this region is estimated as 1:5,000 newborns. These results, together with pedigree analysis, strongly suggest a founder effect accounting for the high frequency of p.H178L mutation in this area. This reinforces the need of a comprehensive community genetics program for this area.

Highlights

► There is a high prevalence (1:5000) of MPS VI in the region of Monte Santo/BA/Brazil. ► We characterized the ARSB gene molecular background of these patients. ► All patients were found to be homozygous for the p.H178L mutation. ► We built haplotypes using intragenic SNPs to check for a possible common origin. ► We reinforce the need of a comprehensive community genetics program for this area.

Introduction

Mucopolysaccharidosis type VI (MPS VI; Maroteaux–Lamy syndrome; OMIN 253200) is a lysosomal storage disease caused by deficiency of arylsulphatase (ARSB, N-acetylgalactosamine-4-sulphatase), which is required for the degradation of dermatan and chondroitin sulphates [1].

The isolation and characterization of human ARSB cDNA [2], [3] and the partial elucidation of the human ARSB gene structure [4] have made possible the identification of molecular defects in ARSB gene mutant alleles. The gene for human ARSB has 209 kb (genome.ucsc.edu), it is comprised of 8 exons, ranging in size from 71 to 885 bp. The nascent polypeptide has 533 amino acids [5]. Approximately 140 mutations have been described and several polymorphisms have been identified in the gene sequence [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17].

In Northeast Brazil we identified on the county of Monte Santo (52,360 inhabitants, 350 km far from Salvador, capital of the Bahia state) an increased incidence of several genetic disorders (such as Phenylketonuria and Congenital Hypothyroidism), probably due to relative endogamy and isolation (Fig. 1). Thirteen cases of MPS VI were identified so far in this county, and it is likely that this frequency could be higher, due to patients who are still undiagnosed or died before a diagnosis was established.

To understand the high frequency of this rare syndrome in Monte Santo, the molecular background of these patients was investigated. The aim of this work was to identify the mutation(s) present on the affected families and to define haplotypes using intragenic SNPs.

Section snippets

Patients

Thirteen patients with MPS VI from Monte Santo (Bahia State, Northeast Brazil), being 9 males and 4 females, were diagnosed based on identification of dermatan sulfate in urine and deficiency of ARSB activity in leucocytes. Informed consent was obtained from the patient's parents. We also analyzed 93 patients from the MPS Brazil Network, as explained later.

Mutation detection

Genomic DNA was obtained from peripheral blood collected in EDTA using the salting-out precipitation technique [18]. The polymerase chain

Results

SSCP analysis of the index case (Fig. 2) showed an altered pattern in exon 3 and the p.H178L (533A>T) mutation was detected in homozygosis after sequencing. This mutation abolishes a restriction site for the Hsp92II enzyme. The thirteen patients were screened by RFLP confirming the presence of p.H178L mutation in homozygosis (Table 1). The entire open reading frame of the ARSB gene and all exon–intron boundaries were analyzed by sequencing in the index case to exclude other possible mutations.

Discussion

In this study we identified the p.H178L mutation in a cluster of MPS VI patients from Monte Santo, a county in Bahia state, Northeast Brazil (Fig. 1). According to international studies, the incidence of MPS VI ranges from 1 in 43,261 births in Turkish to 1 in 1,505,160 births in Sweden [20]. An incidence for MPS VI in Brazil has not been published yet, but data from MPS Brasil Network show that MPS VI is not as rare as in other countries (Personal communication).

Monte Santo presents a number

Conclusions

We can conclude that p.H178L mutation, which has so far not been described in other populations, was introduced once in the Monte Santo area and became common on this quite isolated area due to endogamy and consanguinity. The presence of this mutation in homozygosity in all patients who present this autosomal recessive disease supports that a founder effect is a suitable explanation for this finding. Taking into account these results, a comprehensive community genetics program, which could

Conflict of interest

The authors declare that there are no conflicts of interest.

Acknowledgments

This study was supported by institutional (FIPE-HCPA) and Brazilian Institute for Population Medical Genetics (INAGEMP) funds. FMCM is supported by CAPES scholarship. SLS, RG and IVDS receive Research Grants from CNPq.

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