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Mucopolysaccharidosis type VI, is a rare genetic
disease caused by a deficiency of the N-acetylgalactosamine-4-sulfatase enzyme,
also known as aryl sulfatase B. In Colombia, there are 36 known cases, of which
10 are in an indigenous group with an estimated prevalence of 1/1,140,000. New
mutations are published continuously and, to date, 140 have been reported. The
main objective of this study is to characterize, by molecular genetics, two
patients identified in Southwestern Colombia (Department of Cauca) with the
severe form of MPS type VI. A single nucleotide (p.C447F) pathogenic
transversion producing a sense change mutation was found in the two index cases
on exon 8 of the ARSB gene. This
gives rise to the exchange of one amino acid for another on the minor domain of
the enzyme: position 206,029 (T/T) TGT>TTT. An unusual frequency of genetic
diseases is found in the department of Cauca in Colombia. In this study, the
two index patients exhibit the same mutation, suggesting the possibility of a
common ancestral allele, probably due to the relative inbreeding and the
geographical isolation of these regions. The above highlights the importance of
public health policies in our country, genetic counseling, neonatal screening
and identification of new cases in areas where incidence is above average.
Keywords: Lysosomal
diseases, Muco polysaccharidosis type VI, Matoreaux-Lamy syndrome
INTRODUCTION
Mucopolysaccharidosis type VI (MPS VI) or
Maroteaux–Lamy syndrome (OMIM #253200), is a rare genetic disease caused by a
deficiency of the N-acetylgalactosamine-4-sulfatase enzyme, also known as
arylsulfatase B (ARSB) (coded on locus 5q11-13) [1]. This enzyme is involved in
dermatan glycosaminoglycan and chondroitin sulfates catabolism [2]. Incidence
can vary among different populations and geographical regions, ranging from 1
in 238,000 births and 1 in 1,298,000 births [3]. In Colombia, of 36 known
cases, 10 are in an indigenous group (Author data, not published yet). This
equates to an estimated prevalence of around 0.08/100,000 inhabitants for the
general population of Colombia; 2.6/100,000 indigenous people in Colombia and
3.6/100,000 indigenous people in the department of Cauca.
The ARSB
human gene is a 209 kb gene comprised of 8 exons, ranging in size from 71 to
885 bp [1]. It encodes a polypeptide of 533 amino acids [1]. MPS VI results
from several ARSB mutations,
including missense, non-sense, splice site, small deletions, small insertions,
insertion-deletion (indel) and large deletions [4].
A molecular study of 14 Colombian patients
with MPS VI [6] identified 14 mutations (80% with severe phenotype), of which
57% had not been previously reported (p.H111P, p.C121R, p.G446S, p.*534W,
p.S334I, p.H147P, c.900TNG, and c.1531_1553del) and 43% had private mutations
(p.G144R, p.W322*, p.G302R, p.C447F, p.L128del and c.1143-1GNC).
The Department of Cauca in southwestern
Colombia has a total population of 1,355,000 inhabitants. It is characterized
by a high incidence of some genetic disorders (such as muscular dystrophies, osteogenesis
imperfecta and hemoglobinopathies), probably due to the relative inbreeding and
the geographical isolation of these regions. The population of this department
belongs to three large ethnic groups: Afro-Colombians (22.19%), “mestizos” and
white (56.31%) and the Indigenous or Amerindian groups (Paeces, Guambianos and
Ingas, among others) (21.5%). These indigenous populations are some of the
largest in the country (28.7% of the total national indigenous population).
Here, we have identified a total of 16 cases out of the 36 reported in Colombia
for MPS type VI (45% of the cases recorded in this country) (Author data, not
published yet). The frequency reported may be higher, as many patients are not
diagnosed or die before a definitive diagnosis is made.
The main objective of this study is to
characterize, by molecular genetics, two patients identified in southwestern
Colombia with the severe form of MPS type VI.
MATERIALS AND
METHODS
Sample and family
data collection
All the 16 patients found in the Department
of Cauca have been characterized clinically and confirmed by means of enzymatic
activity test in leukocytes. Two of these patients, coming from the
municipalities of Totoró and Piendamó, were considered index cases for
assessment and clinical care under our study in the Pediatrics Service of San
José University Hospital in Popayan, Cauca. After obtaining the authorization
of the institutional Ethics Committee and the informed consent from the father,
mother or legal guardian of the children, a molecular characterization of the
mutation was performed on the index cases (DNA extraction, PCR amplification
and gene sequencing (ABI PRISM*3100 Genetic Analyzer) for each exon).
RESULTS
A single nucleotide (p.C447F) pathogenic
transversion producing a sense change mutation was found in the two index cases
on exon 8 of the ARSB gene, using the
ALAMUT software (version 2). This gives rise to the exchange of one amino acid
for another on the minor domain of the enzyme: position 206,029 (T/T)
TGT>TTT; mutation p.C447F (Figures 2
and 3).
DISCUSSION
In the crystallographic structure of the
enzyme (PDB code 1FSU), the lateral chain of the C447 amino acid appears as
forming a disulphide bridge with the lateral chain of the Cys405 amino acid.
This is an important secondary structural element, and when it is lost in the
p.C477F mutation, it affects the folding ability of this domain and,
consequently, its secondary structure.
The biological function of the minor domain
appears to be related with enzyme solubility, molecular recognition of the
substrates to be hydrolyzed and bioavailability in the different organs, cells
and intracellular media. The mutation described results in a structural change
in the minor domain, with a loss of enzyme selectivity for its substrates, as
well as for changes in its solubility in the different biological media,
resulting in different bioavailability when compared to the native protein. The
three-dimensional structure of the major domain (amino acids 1-382) should not
be affected by this mutation. Nevertheless, these functions must be severely
affected by the mutation as a result of the structural change in the minor
domain. This should lead to a loss of selectivity of the enzyme for its
substrates.
An unusual frequency of genetic diseases is
found in the department of Cauca in Colombia, which is probably underestimated
due to misdiagnosis, lack of diagnosis and patients dying before diagnosis. In
this study, the two index patients exhibit the same mutation, suggesting the
possibility of a common ancestral allele, probably due to the relative
inbreeding and the geographical isolation of these regions. The above
highlights the importance of public health policies in our country, genetic
counseling, neonatal screening and identification of new cases in areas where
incidence is above average.
CONCLUSION
The two index cases from different
municipalities present the same homozygous p.C447F mutation. Given the low rate
of migration and high frequency of endogenic marriages; the finding of the same
mutation, suggests the possibility of a common ancestral allele and enhances
the importance of molecular diagnosis in the study of gene hereditary diseases,
allowing genotype-phenotype correlation which may predict severity and enzyme
replacement success.
FUNDING
Fundación Pública Galega de Medicina Xenómica
and Biomarín Colombia provided support for this study.
ACKNOWLEDGMENT
1. Litjens
T, Baker EG, Beckmann KR, Morris CP, Hopwood JJ, et al. (1989) Chromosomal
localization of ARSB, the gene for human N-acetylgalactosamine-4-sulphatase.
Hum Genet 82: 67-68.
2. Valayannopoulos
V, Nicely H, Harmatz P, Turbeville S (2010) Mucopolysaccharidosis VI. Orphanet
J Rare Dis 5: 5.
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HY, Chuang CK, Wang CH, Chien YH, Wang YM, et al. (2016) Long-term galsulfase
enzyme replacement therapy in Taiwanese mucopolysaccharidosis VI patients: A
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T, Hopwood JJ (2001) Mucopolysaccharidosis type VI: Structural and clinical
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PN, Kayserili H, Guven Y, Kantaputra W, Balci MC, et al. (2014) Clinical manifestations
of 17 patients affected with mucopolysaccharidosis type VI and eight novel ARSB
mutations. Am J Med Genet Part A 164: 1443-1453.
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GA, Ayala-Ramírez P, Prieto JC, García-Robles R, Acosta JC (2016) Molecular
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