Mutations in the Delta1-pyrroline 5-carboxylate dehydrogenase gene cause type II hyperprolinemia.
We surveyed Delta1-pyrroline 5-carboxylate dehydrogenase genes from four patients with hyperprolinemia type II using RT-PCR amplification, genomic PCR amplification and direct sequencing. We found four mutant alleles, two with frameshift mutations [A7fs(-1) and G521fs(+1)] and two with missense mutations (S352L and P16L). To test the functional consequences of three of these, we expressed them in a P5CDh-deficient strain of Saccharomyces cerevisiae . In contrast to wild-type human P5CDh, yeast expressing S352L and G521fs(+1) failed to grow on proline and had no detectable P5CDh activity. The P16L allele, however, produced fully functional P5CDh and subsequent analysis suggests that it is polymorphic in the relevant (Spanish) population. Interestingly, the G521fs(+1) allele segregates in the large Irish Traveller pedigree used to define the HPII phenotype. To our knowledge, this is the first description of the molecular basis for this inborn error.
Institute for Genetic Medicine, Department of Pediatrics, Predoctoral Training Program in Human Genetics and Molecular Biology and Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
M T
MT
Geraghty
D
D
Vaughn
A J
AJ
Nicholson
W W
WW
Lin
G
G
Jimenez-Sanchez
C
C
Obie
M P
MP
Flynn
D
D
Valle
C A
CA
Hu
D050842:1-Pyrroline-5-Carboxylate Dehydrogenase; D000483:Alleles; D000592:Amino Acid Metabolism, Inborn Errors / Q000145:classification / Q000201:enzymology* / Q000235:genetics*; D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D015870:Gene Expression; D006801:Humans; D008297:Male; D009154:Mutation; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011392:Proline / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development / Q000378:metabolism
D017931:DNA Primers; D018076:DNA, Complementary; D011392:Proline; D050842:1-Pyrroline-5-Carboxylate Dehydrogenase; C494240:ALDH4A1 protein, human; D000587:Oxidoreductases Acting on CH-NH Group Donors