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Human Molecular Genetics Pages 403-406
Dopa-responsive dystonia in British patients: new mutations of the GTP-cyclohydrolase I gene and evidence for genetic heterogeneity
Introduction
Results
Discussion
Materials And Methods
   Patients
   PCR amplification
   Sequencing
ACKNOWLEDGEMENTS
Abbreviations
References

Dopa-responsive dystonia in British patients: new mutations of the GTP-cyclohydrolase I gene and evidence for genetic heterogeneity

Dopa-responsive dystonia in British patients: new mutations of the GTP-cyclohydrolase I gene and evidence for genetic heterogeneity Oliver Bandmann1, Torbjoern G. Nygaard2, Robert Surtees3, C. David Marsden1, Nicholas W. Wood1,* and Anita E. Harding1,[dagger]

1University Department of Clinical Neurology (Neurogenetics and Movement Disorders Section), Institute of Neurology, Queen Square, London, UK, 2Department of Neurology, Columbia University, New York, USA and 3Institute of Child Health, Guilford Street, London, UK

Received November 22, 1995; Revised and Accepted December 22, 1995

Dopa-responsive dystonia (DRD) was originally described in a series of Japanese patients, but is now increasingly recognized in other countries. Recently the GTP cyclohydrolase I (GTPCH) gene was isolated as the first causative gene for dopa-responsive dystonia (DRD). Mutations were identified in three Japanese families with autosomal dominantly inherited DRD and in one sporadic Japanese patient. Characterisation of the exon-intron boundaries of this gene has now allowed the analysis of mutations at the level of genomic DNA. Amplifying all six exons, we analyzed the GTPCH gene in nine British families with 33 affected family members and in three sporadic cases and found six new mutations. Only point mutations were found, causing a stop codon in one family and an amino acid change in highly conserved regions of the gene in a further four families and in one sporadic case. None of these mutations were detected more than once and none of the mutations previously described were found in our patients. No mutations were identified in four families and in two sporadic cases.

INTRODUCTION

The first description of a British patient with what is now called dopa-responsive dystonia (DRD) dates back to 1947 (1 ). Segawa first suggested this was a new disease entity in the early 1970s (2 ) and noted the typical clinical features of lower limb dystonia with diurnal fluctuation. This phenotype is most common in patients with an early age of onset (3 ). However, it is now clear that later in life it may resemble idiopathic Parkinson's disease (4 ). This paper broadens the phenotype of genetically proven DRD to include severe `athetoid cerebral palsy'.

Both familial and sporadic cases have been described (3 ). In families with autosomal-dominant inheritance, the penetrance appears to be 30% (5 ), the female to male ratio being approximately 3:1 (6 ). Using anonymous markers, Nygaard et al. found linkage to chromosome 14q in three families with autosomal- inherited DRD, the gene was mapped to the region between D14S269 and D14S63 (14q11-q24.3) (7 ). Linkage to 14q has since been confirmed in other families with autosomal-dominant DRD (8 ,9 ).

Ichinose et al. identified the GTP-Cyclohydrolase I (GTPCH) gene, which maps to 14q21-22 (10 ), as a causative gene for DRD (11 ). Four mutations of the GTPCH gene were detected and the activity of this enzyme in mononuclear blood cells was markedly reduced in patients carrying these mutations. Affected members of a fifth family did not show a mutation, despite decreased activity of the GTPCH in mononuclear blood cells in affected members and despite evidence for linkage to 14q21-22, the GTPCH gene locus, in this family.

GTPCH is the initial and rate-limiting enzyme in tetrahydrobiopterin (BH4) synthesis (12 ). It converts GTP to dihydroneopterin triphosphate which is the substrate for 6-pyruvoyl-tetrahydropterin synthase. Three aromatic acid monooxygenases-phenylalanine, tyrosine and tryptophan hydroxylase-require BH4 as an essential cofactor. Tyrosine hydroxylase (TH) is the initial and rate-limiting enzyme in dopamine (DA) synthesis (13 ). In DRD, the disturbed function of this enzyme, resulting in decreased levels of DA, can therefore be explained by lack of the necessary cofactor BH4, which is due to GTPCH deficiency.

An autosomal recessive form of the disease has also been described; in one family, two affected siblings were homozygous for a point mutation in exon 11 of the TH gene (14 ,15 ). These inital reports suggest genetic heterogeneity of DRD, although adequate clinical details on the patients are lacking.

We describe here the results of GTPCH sequence analysis in British patients with DRD. The GTPCH gene was sequenced in nine families with 33 affected members and three sporadic cases.

RESULTS

Six different heterozygote mutations were found. In three families there were affected members in two or more generations. Two families had affected sibling pairs only and there was one sporadic case (see Fig. 1 ). These abnormalities were all point mutations and no deletions or insertions were detected in any of the cases examined. All base pair changes were within highly conserved regions of the GTPCH gene (16 ). In family Ha, the C -> T change created a stop codon at codon 216. In families Ro (see Fig. 2 ), Mo and Sm as well as in patient Be, the mutations caused a non-conservative amino acid change, whilst the point mutation in codon 224 of family Hu caused a conservative change from lysine to arginine (see Table 1 ).


Figure 1.(a) A -> C (His153Pro) mutation in family Ro; (b) control sequence.


Figure 2.Families with detected mutation. *sequenced family members.

The mutations were distributed through all the exons except exon 4. None of the mutations detected by Ichinose et al. (11 ) were found. In family Mo, the mutation lay within the same amino acid codon as one of the mutations described by Ichinose et al. (11 ), but caused a different amino acid change (see Table 1 ).

No mutations were detected in three families with affected members in more than one generation, as well as in one family with two affected sibs, and two sporadic cases.

DNA from family members not affected with DRD was only available in family Ha and Hu. In family Ha, the mutation segregated with the disease and no cases of reduced penetrance were found. In family Hu, patient II-3 and II-4, both suffering from a clinical phenotype resembling athetoid cerebral palsy, showed the Lys224Arg mutation, whilst patient II-1 with Friedreich's ataxia did not show the mutation described in the affected members. Patient II-2 was unavailable for sequencing.

DISCUSSION

We have found six new mutations of the GTPCH gene in British patients with DRD. While the mutation in family Ha caused a stop codon, the other five mutations caused an amino acid change, which was non-conservative in all families but family Hu. The Lys224Arg mutation in family Hu is still considered to be pathogenic, since examination of the cerebrospinal fluid (CSF) showed decreased neopterin levels in the two examined family members with the mutation (patient II-3 and patient II-4), whilst neopterin levels in the CSF were normal in the family member II-1, who did not show the mutation (see Table 2 ). However, it cannot be excluded that this conservative mutation is merely in linkage equilibrium with a pathogenic mutation in the non-coding region of the gene and therefore not itself pathogenic. The dramatic response of patient II-4 to L-dopa treatment underlines the importance to consider DRD in the differential diagnosis of patients presenting with a phenotype resembling athetoid cerebral palsy.

None of these mutations were detected more than once and none of the mutations described by Ichinose et al. (11 ) were found in our patients. A common mutation of the GTPCH, responsible for all or at least a majority of all cases with DRD due to GTPCH deficiency has not been found either in the Japanese population or in the British population we have examined. This is surprising in a rare autosomal-dominant gene defect, where a founder mutation in the population examined might have been expected. It also has implications for the diagnostic testing of patients (see below). The mutations are not clustered in or around the active site of the enzyme, as described in (17 ).

Table 1 . Identified mutations of the GTP cyclohydrolase I gene
Exon

 Nucleotide

 Protein

 Patient/

 Number of
 

 alteration

 alteration

 family

 affected patients
Exon 1

 ATG GAG -> ATG GG GAG*

 frame shift

 Sa

 2
 

 CGG -> CCG

 Arg88Pro

 Mo

 2
 

 CGG -> TGG*

 Arg88Trp

 K

 3
Exon 2

 GAC -> GTC*

 Asp134Val

 Su

 2
Exon 3

 CAT -> CCT

 His153Pro

 Ro

 2
Exon 5

 GGA -> GAA*

 Gly201Glu

 N

 1
 

 GGG -> AGG

 Gly203Arg

 Be

 1

Exon 6

 CGA -> TGA

 Arg216Stop

 Ha

 2
 

 AAA -> AAG

 Lys224Arg

 Hu

 2
 

 TTC -> TCC

 Phe234Ser

 Sm

 2
*as described in (11), altered bases underlined.

Table 2 . Neopterin concentration in the CSF of family Hu
 

 Pat. II-1

 Pat. II-3

Pat. II-4

 Control values
Neopterin

7.9

 5.9

 4.3

 7-65 nmol/l (20)
Lys224Arg mutation

negative

positive

 positive

  

Mutations were not detected in three familes with DRD and autosomal-dominant inheritance, in whom linkage data were consistent with co-segregation of a chromosome 14q region in the affected family members. As mentioned above, Ichinose et al. (11 ) were also unable to detect a mutation in one of the four families they studied despite evidence for linkage to 14q and decreased enzyme activity of the GTPCH. So far, there is no clear explanation for these negative findings. A possible explanation is that the mutations lie outside the coding region of the GTPCH gene, but inside one of the regulatory regions at the 5' end or 3' end of the gene. This is compatible with positive linkage to the locus.

In addition to the three families mentioned above, we have not found mutations in a family with two affected sibs and in two sporadic cases. In these cases, the lack of detected mutations might be due to any of the possible reasons discussed above. Alternatively, these patients could have the autosomal-recessively inherited form of DRD due to mutations of the TH gene (14 ,15 ). Our finding of mutations in the GTPCH gene in two sib-pairs and one sporadic case shows that it is not possible to tell from the family history, whether mutations of the GTPCH gene or the TH gene underlie the clinical picture of DRD in isolated cases or affected sibs.

Our results have important implications for the possible diagnostic role of the GTPCH gene testing in clinically suspected cases of DRD. Since common mutations of the GTPCH gene do not exist, it becomes necessary to sequence the entire GTPCH gene to detect possible mutations. The GTPCH gene is only expressed in very low levels in blood and fresh blood samples from patients are not always available. It is therefore unlikely that RT-PCR amplification and complete sequencing of the GTPCH gene in a single assay will replace the separate amplification of each of the six exons from genomic DNA. This makes the screening of the GTPCH gene in suspected DRD both very time-consuming and expensive. Even if this is done, mutations will not be detected in all cases investigated. It is therefore unlikely that genetic testing for DRD will be introduced into routine clinical practice.

In summary, this paper confirms the importance of GTP cyclohydrolase I as a cause of DRD. There is no evidence of a founder effect and 10 different mutations within the coding region have been detected to date. In addition, we have expanded the range of genetically proven cases of DRD to a new phenotype of DRD resembling athetoid cerebral palsy.

MATERIALS AND METHODS

Patients

Nine families with 33 affected members and three sporadic cases were included in this study. Six of the families had affected members in at least two generations so that autosomal-dominant inheritance could be presumed. In the remaining three families, only members of one generation were affected. It was therefore unclear in these families, whether DRD had been inherited in an autosomal-dominant fashion with reduced penetrance or in an autosomal-recessive fashion. In most cases, the affected members of the families presented with typical features of DRD which have been described elsewhere (3 ). In family Hu, however, only patient II-2 showed typical DRD with childhood onset dystonia of the lower limbs, and in patient II-3 and II-4, history and findings on clinical examination were suggestive of athetoid cerebral palsy. Patient II-1 coincidentally suffered from Friedreich's ataxia. Patient II-2 and II-4 responded dramatically to L-dopa and some improvement was also observed in patient II-3. However, this treatment did not cause any improvement in patient II-1.

PCR amplification

DNA was extracted from blood using standard techniques. For exon 1, a nested polymerase chain reaction (PCR) was developed with a reaction volume of 25 µl for the first PCR and 100 µl for the second PCR, containing 100 ng of genomic DNA in the first and 2 µl of the first PCR product in the second PCR. 30 pmol of each primer, 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 1.5 mM MgCl, 10% DMSO and 2.5 U of Taq polymerase were used in each reaction volume. Conditions for the first PCR were: one cycle at 94oC for 3 min, followed by 30 cycles of 94oC for 30 s, 55oC for 30 s and 72oC for 30 s, followed by a final extension time of 10 min at 72oC. For the nested PCR, the annealing temperature was 57oC, conditions being otherwise identical to the the first PCR. For the first PCR, primers were used as previously described (18 ). The sequence of the primers for the second PCR were: 5' TCC CGA ACG GCA GCG GCT and 5' TCC CGA ACG GCA GCG GCT. For exon 2-6, primers and PCR conditions were used as previously reported (18 ).

Sequencing

Products of the PCR reaction were purified with Magicprep (Promega). For exon 1, the purified products were rendered single stranded by capture onto streptavidin coated beads (Dynal). Direct sequencing was performed with fluorescent labelled dye terminators using a T7 sequencing kit (Applied Biosystems). The internal primers used for the sequencing of exon 1 were: 5' AGC GAG CTC AGG ATG GAC and 5' CAG CAG GCC GGC GGA GAA G. Sequencing of exon 2-6 was performed using the Taq DyeDeoxy terminator sequencing kit (Applied Biosystems). PCR products of exon 2-6 were sequenced directly with the same primers as used for amplification. The reactions were performed according to the protocol supplied by the manufacturer. The sequence reactions were run and analyzed, using an automatic sequencer (ABI 373A). Both strands of each sample were sequenced twice and a control was included in each sequencing run. Sequences were compared with the published sequence (GenBank accession number: U15256-15259). CSF neopterin levels were measured by high pressure liquid chromatography (HPLC) as previously described (19 ).

ACKNOWLEDGEMENTS

We thank all the patients and the referring consultants. Financial support of the Deutsche Forschungsgemeinschaft (DFG) and the Parkinson's Disease Society (UK) is gratefully acknowledged.

ABBREVIATIONS

DRD, dopa-responsive dystonia; CSF, cerebrospinal fluid; TH, tyrosine hydroxylase; SN, substantia nigra; DA, dopamine; GTPCH, GTP cyclohydrolase I; BH4, tetrahydrobiopterin.

REFERENCES

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7 Nygaard,T.G., Wilhelmsen,K.C., Risch,N.J., Brown,D.L., Trugman,J.M., Gilliam,T.C., Fahn,S. and Weeks,D.E. (1993) Linkage of dopa-responsive dystonia (DRD) to chromosome 14q. Nature Genet., 5, 386-391.

8 Tanaka,H., Endo,K., Tsuyi,S., Nygaard,T.G., Weeks,D.E., Nomura,Y. and Segawa,M. (1995) The gene for hereditary progressive dystonia with marked diurnal fluctuation (HPD) maps to chromosome 14q. Ann. Neurol., 37, 405-408.

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10 Thöny,B., Heizmann,C.W. and Mattei,M.-G. (1995) Human GTP-Cyclohydrolase I gene and sepiapterin reductase gene map to region 14q21-q22 and 2p14-p12, respectively, by in situ hybridization. Genomics, 26, 168-170.

11 Ichinose,H., Ohye,T., Takahashi,E., Seki,N., Hori,T., Segawa,M., Nomura,Y., Endo,K., Tanaka,H., Tsuji,S., Fujita,K. and Nagatsu,T. (1994) Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene. Nature Genet., 8, 236-241.

12 Kaufman,S. (1959) Studies on the mechanism of the enzymatic conversion of phenylalanine to tyrosine. J. Biol. Chem., 234, 2677-2682.

13 Nagatsu,T., Levitt,M. and Udenfriend,S. (1964) Tyrosine hydroxylase: the initial step in norepinephrine biosynthesis. J. Biol. Chem., 239, 2910-2917.

14 Lüdecke,B., Dworniczak,B. and Bartholome,K. (1995) A point mutation in the tyrosine hydroxylase gene associated with Segawa's syndrome. Hum. Genet., 95, 123-125.

15 Knappskog,P.M., Flatmark,T., Mallet,J., Lüdecke,B. and Bartholome,K. (1995) Recessively inherited L-DOPA-responsive dystonia caused by a point mutation (Q381K) in the tyrosine hydroxylase gene. Hum. Mol. Genet., 4, 1209-1212.

16 Togari,A., Ichinose,H., Matsumoto,S., Fujita,K. and Nagatsu T. (1992) Multiple mRNA forms of human GTP cyclohydrolase. Biochem. Biophys. Res. Commmun., 187, 359-365.

17 Nar,H., Huber,R., Meining,W., Schmid,C., Weinkauf,S., Bacher,A. (1995) Atomic structure of GTP cyclohydrolase I. Structure, 3, 459-466.

18 Ichinose,H., Ohnye,T., Matsuda,Y., Hori,T., Blau,N., Burlina,A., Rouse,B., Matalon,R., Fujita,K. and Toshiharu,N. (1995) Characterization of mouse and human GTP cyclohydrolase I genes. J. Biol. Chem., 270, 10062-10071.

19 Howells,D.W., Smith,I., Hyland,K. (1986) Estimation of tetrahydrobiopterin and other pterins in cerebrospinal fluid using reversed phase HPLC with electrochemical and fluorescence detection. J. Chromatogr., 381, 285-294.

20 Hyland,K., Surtees R., Heales,S.J.R., Bowron,A., Howells,D.W., Smith,I. (1993) Cererbrospinal fluid concentrations of pterins and metabolites of serotonin and dopamine in a pediatric reference population. Pediatr. Res., 34, 10-14.

*To whom correspondence should be addressed[dagger]Deceased September 11, 1995

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