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Carrier of Hunter Disease J Med Genet: First Published As 10.1136/Jmg.34.2.137 on 1 February 1997

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Carrier of Hunter Disease J Med Genet: First Published As 10.1136/Jmg.34.2.137 on 1 February 1997 JMed Genet 1997;34:137-140 137 Germline and somatic mosaicism in a female carrier of Hunter disease J Med Genet: first published as 10.1136/jmg.34.2.137 on 1 February 1997. Downloaded from Roseline Froissart, Irene Maire, Vronique Bonnet, Thierry Levade, Dominique Bozon Abstract by haplotype, enzyme analysis, and mutation Carrier detection in a mucopolysacchari- identification. This study led to the identifica- dosis type II family (Hunter disease) tion of germline and somatic mosaicism in the allowed the identification of germline and proband's mother. somatic mosaicism in the patient's mother: the R443X mutation was found in Material and methods a varying proportion in tested tissue (7% CASE REPORT in leucocytes, lymphocytes, and lymphob- The patient was the first child of healthy lastoid cells, and 22% in fibroblasts). The parents. The diagnosis was suspected at 3 years proband's sister carries the at risk allele but was assessed at 6 years; increased excretion (determined by haplotype analysis), but of glycosaminoglycans (heparan sulphate and not the mutation. In sporadic cases of X dermatan sulphate) in urine was found as well linked diseases, germline mosaicism of as IDS deficiency in serum. He is now 17 years the proband's mother is difficult to ex- old and presents with coarse facial features, clude and should be considered in genetic enlarged tongue, kyphosis, joint stiffness that counselling. has required surgery, short stature, hepato- (JMed Genet 1997;34:137-140) splenomegaly, cardiopathy (mitral and aortic insufficiency, mitral stenosis), deafness, and Keywords: mucopolysaccharidosis type II; mosaicism; mental retardation. The pedigree of the family mutation. is shown in fig 1. Hunter disease or mucopolysaccharidosis type IDS ACTIVITY II (MPS II) is an X linked lysosomal storage IDS activity was determined using the reagent disease resulting from the deficiency of kit provided by The Hospital for Sick Children, iduronate-2-sulphatase (IDS, EC 3.1.6.13).' Toronto, Canada as previously described.'6 7 The IDS gene has been mapped to Xq28.2 A POLYMORPHIC full length cDNA clone containing an open MARKERS http://jmg.bmj.com/ reading frame of 1650 bp has been isolated and Genomic DNA was extracted from leucocytes, sequenced.3 The IDS gene spans 24 kb and lymphocytes, fibroblasts, or lymphoblastoid contains nine exons4 5 and has been completely cells according to Jeanpierre.'" Genomic DNA sequenced6 (GenBank accession number from leucocytes was digested by StuI, TaqI, and L4358 1). A pseudogene located 20 kb distal to BanI. Southern blotting was carried out using the active gene has been characterised6 and is standard procedures. DNA probes, radiola- Centre d'Etudes des involved in recombinations with the IDS belled with a&P-dCTP by random priming, Maladies on October 2, 2021 by guest. Protected copyright. Metaboliques, gene.7 8 Various IDS locus alterations have included: IDS cDNA (1.7 kb NotIlXhoI Biochimie Batiment D, been described,9'-2 such as large deletions and fragment from the cDNA clone pB2Sc17 con- Hopital Debrousse, 29 rearrangements, but about 80% of the muta- taining the complete coding region of IDS), Rue Soeur Bouvier, tions are point mutations, minor deletions, or probe II-10 at locus DXS466,'9 probe U6.2- 69322 Lyon Cedex 05, insertions. Most of them are private except for 20E at locus DXS304,2' and probe VK21A at France some that more locus DXS296.2' Haplotypes were R Froissart frequently occur on CpG determined I Maire dinucleotides. with the StuI intragenic polymorphism (in V Bonnet Female carriers of MPS II are asymptomatic intron 8) and three extragenic polymorphisms, D Bozon though they often show decreased levels of IDS BanI (U6.2-20E) and TaqI (II-10 and activity in serum or leucocytes or both. Cloned VK21A). Laboratoire de fibroblasts'3 or hair roots'4 have also been stud- A microsatellite at locus DXS1113, located Biochimie Maladies ied for carrier detection. However, 10 kb distal to the IDS gene, was analysed as Metaboliques, CJF attempts to INSERM 9206, CHU identify carriers by enzyme assays have often described by Weber et al.22 Rangueil, 1 Avenue led to ambiguous results because of non- Jean Poulhes, 31054 random X inactivation. Indirect genotype AMPLIFICATION OF GENOMIC DNA Toulouse Cedex, analysis using intragenic and closely linked Exon 9 was amplified as a 580 bp fragment France flanking polymorphisms, combined with enzy- with oligonucleotides 5I: 5'- T Levade matic and pedigree analyses, allows carrier CCATTCTGCTCTGTCGCTTC-3' (nt Correspondence to: detection in some but not all families.'5 Identi- 54371-54352 in intron 8) and V6: 5'- Dr Froissart. fication of the mutation in a patient with MPS CAAAACGACCAGCTCTAACTC-3' (nt II allows fast and reliable carrier detection in 53792-53812 in exon 9). PCR conditions Received 15 May 1996 related at Revised version accepted for risk females. were: 94°C for 30 seconds, 61°C for 30 publication The carrier status of females in a family with seconds, and 72°C for 45 seconds, for 30 26 September 1996 an isolated case of Hunter disease was studied cycles. 138 Froissart, Maire, Bonnet, Levade, Bozon nd nd 580 bp band instead of the normal 410 and nd nd 170 bp bands. a b nd nd J Med Genet: first published as 10.1136/jmg.34.2.137 on 1 February 1997. Downloaded from nd, nd Quantitative PCR <,01 ~~~~~~~(-)To assess the relative proportion of mutant (R443X) and normal DNA, exon 9 was 2 2 ampli- a c fied as described previously for 29 cycles, and 1 2 2 jCi of '32P-dCTP was added before the last 11 * 01||1 cycle. Radiolabelled PCR products were di- gested by TaqI and separated on an 8% acryla- mide non-denaturing gel. The gel was dried 2 2 2 and autoradiographed. Radioactivity of each band was quantified by scanning the film. Then 2 2 2 1 1 1 the bands were cut from the dried gel and (+) (-) radioactivity content estimated by scintillation counting. Haplotype: TaqlNK21A R443X mutation: Presence (+) Results Stul/IDS Absence (-) Microsatellite DXS1 113 Varying proportion (+/-) IDS ACTIVITY Taql/II-1 0 IDS activity was borderline in the mother's Banl/U6.2-20E leucocytes and within the normal range in serum and lymphoblastoid cells (table 1). IDS nd: not determined activity was found to be normal in the grandmother's leucocytes and serum and in the Figure 1 Family pedigree showing the segregation of the haplotypes and R443X sister's lymphoblastoid cells. Study of 25 mutation. fibroblast clones from the sister did not show Amplification of genomic DNA from hair any deficient clone (data not shown). roots was performed as follows: each hair root was rinsed in distilled water and in 100% etha- HAPLOTYPE ANALYSIS nol, then heated to 94°C for 30 minutes in The results of haplotype analysis are shown in PCR buffer. Amplification was performed with fig 1: microsatellite DXS 1 1 13 was the only two sets of primers: 5'IN6 and microsatellite informative marker. Unexpectedly, the pa- DXS 1 1 13 primers22 for 30 seconds at 940C, 45 tient's sister had inherited from her mother the seconds at 600C, and one minute at 72°C, for same X chromosome as her brother. 30 cycles. MUTATION R443X EXON 9 SEQUENCING Exon 9 was systematically sequenced (presence After amplification, PCR products were puri- of several mutational hot spots9 10 12 ), allowing http://jmg.bmj.com/ fied on a 5% acrylamide gel and directly the identification ofthe R443X mutation in the sequenced with the Thermosequenase cycle patient's genomic DNA. The presence of this sequencing kit (Amersham) using y'3P-ATP. mutation was tested in the mother's leucocytes by TaqI digestion of exon 9 PCR product: this R443X MUTATION ANALYSIS showed an abnormal distribution of digested Allele specific oligonucleotide (ASO) and undigested PCR products (not shown). The mother's genomic DNA extracted from hybridisation on October 2, 2021 by guest. Protected copyright. The PCR products were analysed by ASO various sources (leucocytes, lymphocytes, lym- hybridisation. ASO used for the detection of phoblastoid cells, fibroblasts, and hair roots) the normal and mutant R443X sequences were was analysed by ASO hybridisation to test the hypothesis of somatic mosaicism: the mutant 5'-AGCATTTTCGATTCCG-3' and 5'- AGCATTTTTGATTCCG-3' respectively. allele was present with a low and varying inten- was not in Washing conditions were 5 x SSC at 37°C for sity (fig 2). The mutation detected 2 x 10 minutes, and 2 x SSC at 420C for 3 x 15 the grandmother's leucocytes nor in the leuco- cytes of the sister who had inherited the at risk minutes. haplotype. DNA from 35 separate hair roots of the TaqI digestion mother was used as template for PCR and The R443X mutation abolishes a TaqI site. R443X analysis: only one of them hybridised After digestion of the PCR products, the muta- with both normal and mutant probes. Micro- tion is detected by the presence of an abnormal satellite analysis (DXS 1 1 13) was performed on of Table 1 IDS activity in various samples of the patient and his family each hair root and confirmed the presence the two alleles (mother's karyotype 46,XX). Serum Leucocytes Lymphoblastoid cells The relative proportion of mutant and (pmol. h-'. ml-') (pmol. h-'. mg') (pmol.h-'.mg') normal DNA in the mother's cells was assessed Patient 0.5 by quantitative PCR (fig 3). In control DNA, Mother 1355 77 44 the 410 and 170 bands were Sister 62 only bp detected, Grandmother 1785 152 and in the DNA from an obligate carrier radio- Control 1301 118 44 activity of the abnormal 580 bp band repre- Normal 1185-1900 75-158 20-65 sented about 50% of the total radioactivity, as range expected.
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