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
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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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