Identification of a common mutation in mucopolysaccharidosis IVA: correlation among genotype, phenotype, and keratan sulfate.
Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disorder caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Mutation screening of the GALNS was performed by genomic PCR and direct sequence analyses in 20 MPS IVA patients from Latin America. In this study, 12 different gene mutations including nine unreported ones were identified in 16 severe and four attenuated patients and accounted for 90.0% of the unrelated mutant alleles. The gene alterations were missense mutations except one insertion. Six recurrent mutations, p.A75G, p.G116S, p.G139S, p.N164T, p.R380S, and p.R386C, accounted for 5.0, 10.0, 5.0, 7.5, 5.0, and 32.5% of the unrelated mutant alleles, respectively. The p.R386C mutation was identified in all Latin American populations studied. Eleven mutations correlated with a severe form, while one mutation, p.R380S, was associated with an attenuated form. MPS IVA patients had an elevation of urine and plasma keratan sulfate (KS) concentrations compared with those of the age-matched control. KS concentrations in severe patients were higher than those in attenuated patients. These data provide evidence for extensive allelic heterogeneity and presence of a common mutation in Latin American patients. Accumulation of mutations with clinical description and KS concentration will lead us to predict clinical severity of the patient more precisely.
Tomatsu
Shunji
S
Department of Pediatrics, Pediatric Research Institute, Saint Louis University, 3662 Park Ave., St Louis, MO, 63110-2586, USA. tomatsus@slu.edu.
Dieter
Tatiana
T
Medical Genetics Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, RS, Brazil.
Schwartz
Ida V
IV
Medical Genetics Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, RS, Brazil.
Sarmient
Piedad
P
Institute of Inborn Errors of Metabolism, Javeriana University, Bogota, Colombia.
Giugliani
Roberto
R
Medical Genetics Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, RS, Brazil.
Barrera
Luis A
LA
Institute of Inborn Errors of Metabolism, Javeriana University, Bogota, Colombia.
Guelbert
Norberto
N
CEMECO, Centro de Estudio de las Metabolopatias Congenitas, Hospital de Ninos de Cordoba, Cordoba, Argentina.
Kremer
Raquel
R
CEMECO, Centro de Estudio de las Metabolopatias Congenitas, Hospital de Ninos de Cordoba, Cordoba, Argentina.
Repetto
Gabriela M
GM
Facultad de Ciencias de la Salud, Universidad del Desarrollo-Clinica Alemana, Santiago, Chile.
Gutierrez
Monica A
MA
Department of Pediatrics, Pediatric Research Institute, Saint Louis University, 3662 Park Ave., St Louis, MO, 63110-2586, USA.|Institute of Inborn Errors of Metabolism, Javeriana University, Bogota, Colombia.
Nishioka
Tatsuo
T
Department of Pediatrics, Pediatric Research Institute, Saint Louis University, 3662 Park Ave., St Louis, MO, 63110-2586, USA.
Serrato
Olga Peña
OP
Department of Pediatrics, Pediatric Research Institute, Saint Louis University, 3662 Park Ave., St Louis, MO, 63110-2586, USA.
Montaño
Adriana Maria
AM
Department of Biosystems Science, The Graduate University for Advanced Studies, Kanagawa, Japan.
Yamaguchi
Seiji
S
Department of Pediatrics, Shimane University, Izumo, Japan.
Noguchi
Akihiko
A
Department of Pediatrics, Pediatric Research Institute, Saint Louis University, 3662 Park Ave., St Louis, MO, 63110-2586, USA.
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002811:Chondroitinsulfatases / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers; D005260:Female; D005787:Gene Frequency; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007632:Keratan Sulfate / Q000097:blood / Q000652:urine; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D010641:Phenotype; D017422:Sequence Analysis, DNA; D013020:South America
D017931:DNA Primers; D007632:Keratan Sulfate; D002811:Chondroitinsulfatases; C102295:GALNS protein, human