GENE ALTERATIONS LEADING TO HYPOXANTHINE- GUANINEPHOSPHORIBOSYL TRANSFERASE DEFICIENCY: GENOTYPE-PHENOTYPE CORRELATION
Neychev VK*, Krastev SR, Mitev VI
*Corresponding Author: Dr. Vladimir K. Neychev: Department of Chemistry and Biochemistry, Medical University, 2 Zdrave str., Sofia 1431, Bulgaria; Tel: +359-889-49-51-25 (personal), +359-2-51-66-528 (office); Fax: +359–2-952-02-07; E-mail: Neychev@dir.bg
page: 51

CONCLUSIONS

The differentiation of the HPRT deficiency into four clinical variants, along with an increased number of avail­able cases, permits an attempt to relate the nature and the location of the gene alterations to a particular clinical variant. Two main conclusions arise from the analysis of the reviewed cases: 1) the determination of deletions, insertions, splice site and nonsense mutations in the HPRT gene permits the comparatively exact prediction of pheno­type, and may be of clinical importance for the prenatal diagnosis of the more severe clinical variants 3 and 4). 2) The location and the nature of the missense mutations provide no precise correlation with a particular clinical variant of the HPRT deficiency, since one and the same mutation, derived from different patients, sometimes result in different clinical variants.

 

Table 3. Mutation resulting in a premature stop codon.

 

 

Clinical
Variant

 

Mutation
(Ref.)

 

Alteration

 

Codon

 

Location

 

Nucleotide
Substitution

 

Amino Acid
Substitution

 

4

 

Fujimi (6)

 

nonsense

 

51

 

exon 3

 

C>T

 

Arg>Stop

 

4

 

RJK1930 (5)

 

nonsense

 

109

 

exon 4

 

C>T

 

Gln>Stop

 

4

 

Paris (7)

 

nonsense

 

153

 

exon 6

 

T>G

 

Tyr>Stop

 

4

 

Almodovar (4)

 

nonsense

 

170

 

exon 7

 

C>T

 

Arg>Stop

 

4

 

RJK974 (8)

 

nonsense

 

170

 

exon 7

 

C>T

 

Arg>Stop

 

4

 

1321 (9)

 

nonsense

 

170

 

exon 7

 

C>T

 

Arg>Stop

 

4

 

North Mymms (10)

 

nonsense

 

170

 

exon 7

 

C>T

 

Arg>Stop

 

4

 

LN40-5 (42)

 

nonsense

 

170

 

exon 7

 

C>T

 

Arg>Stop

 

3

 

GS (43)

 

nonsense

 

170

 

exon 7

 

C>T

 

Arg>Stop

 

 

Table 4. Deletions

 

Clinical
Variant

 

Mutation
(Ref.)

 

Alteration

 

Result

 

3

 

Illinois (3)

 

(–)12-(+)1 deletion

 

13 bp deleted; new initiation codon

 

4

 

LN11E (42)

 

E1

 

one exon deleted

 

4

 

RJK1939 (5)

 

125delT

 

frameshift in exon 2

 

4

 

RJK853 (5)

 

E1-9del

 

whole gene deleted

 

4

 

Cheltenham (10)

 

289-290delGT

 

frameshift in exon 3

 

4

 

RJK1747 (5)

 

317-318delGT

 

frameshift in exon 3

 

4

 

Andorra (4)

 

319-384delAAT...

 

exon 4 deleted

 

4

 

RJK2019 (5)

 

391delT

 

frameshift in exon 5

 

4

 

Brierly Hill (10)

 

617-618delGT

 

frameshift in exon 9

 

4

 

LN-K (42)

 

E5-6del

 

two exons deleted

 

4

 

Murcia (4)

 

333-334delAG

 

frameshift in exon 4

 

4

 

Asturias (4)

 

342delA

 

frameshift in exon 4

 

4

 

RJK2108 (5)

 

156-195delATG...

 

40 bp deleted in exon 3

 

4

 

LN40-1 (42)

 

E4del

 

one exon deleted

 

4

 

RJK1894 (5)

 

514-516delGTT

 

one amino acid coded by exon 7 lost

 

4

 

RJK894 (5)

 

643-663delAAA...

 

21 bp deleted in exon 9

 

4

 

Michigan (18)

 

535-537delGTT

 

Val179 lost

 

4

 

LN28 (42)

 

247-248delAA

 

frameshift in exon 3

 

4

 

Henryville (24)

 

IVS-V,+1delG

 

splice error; 66 bp of 15 included; multiple mRNAs

 

3

 

Japan 3 (12)

 

648-698delCAA...

 

51 bp deleted in exon 9

 

Table 5. Insertions.

 

 

Clinical Variant

 

Mutation (Ref.)

 

Alteration

 

Result

 

4

 

Chicago (18)

 

55insT

 

frameshift in exon 2

 

4

 

Zaragoza II (4)

 

100insGG

 

frameshift in exon 2

 

4

 

RJK866 (8)

 

212insG

 

frameshift in exon 3

 

4

 

LN55 (42)

 

219insA

 

frameshift in exon 3

 

4

 

1650 (9)

 

212insG

 

frameshift in exon 3

 

4

 

Cartagene (4)

 

405insA

 

frameshift in exon 6

 

4

 

1656 (9)

 

436insT

 

frameshift in exon 6

 

3

 

RW (40)

 

429insGCA

 

exon 6 codes for an additional amino acid

 

4

 

1266 (9)

 

511insGT

 

frameshift in exon 7

 

4

 

CT (42)

 

288insA

 

frameshift in exon 3

 

4

 

AB (42)

 

405insA

 

frameshift in exon 6




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