MPS II in females: molecular basis of two different cases

Editor—Hunter disease or mucopolysaccharidosis type II (MPS II, MIM 309900) is an X linked recessive disease resulting from deficiency of the lysosomal enzyme iduronate-2-sulphatase (IDS, E.C.3.1.6.13).1 The IDS cDNA has been isolated2 and the genomic region containing the IDS gene and pseudogene has been completely sequenced.3 Phenotypic expression of X linked disorders in females may be the result of an X chromosome anomaly or homozygosity for the mutated gene, but is most frequently the result of skewed X chromosome inactivation. We describe two affected girls, case 1 and case 2, with a mild and a severe form of MPS II, respectively. Both have a normal karyotype but increased dermatan sulphate and heparan sulphate excretion in urine, a marked deficiency of IDS activity, and normal α-L-iduronidase, β-D-glucuronidase, and arylsulphatase A activities in leucocytes and cultured skin fibroblasts ruling out MPS I, MPS VII, and multiple sulphatase deficiency. Molecular studies showed that case 1 is the first case of female MPS II with two mutated IDS genes and that case 2 has a de novo gene rearrangement on the paternal allele (a 3254 bp deletion from intron 7 to intron 8 with an insertion of 20 bp) associated with skewed X inactivation of the normal maternal X chromosome. Case 1 was born into a French gypsy family. At 11 years of age, she presented with hepatomegaly and growth retardation, but had no dysmorphic features, no multiplex dysostosis, no corneal clouding, no cardiovascular disease, no splenomegaly, and no mental retardation, in agreement with a mild form of MPS II. A unique IDS transcript with a T to C substitution at cDNA position 246 in exon 2 (accessionM38371 2) was found in fibroblasts, changing codon CTC (leucine) to CCC (proline), L41P. Sequencing of the PCR products from intron …