ORNITHINE AMINOTRANSFERASE (OAT): EVIDENCE FOR A DISPERSED GENE FAMILY WITH MEMBER(S) LOCALIZED TO Xp11.1 – Xp21.1

Mitchell, Grant A.; Valle, David; Suchanek, Maureen K.; Steel, Gary; Brody, Lawrence C.; Looney, J E; Willard, H.F.

doi:10.1203/00006450-198704010-00751

Cited by 5 publications

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“…To study the cell biology of OAT and the mutations causing GA, we have cloned and sequenced a near full-length human liver OAT cDNA and have determined the structure of the human OAT structural gene, which has 11 exons and spans 22 kilobases (kb) (2). We (2,3) and others (4,5) have shown that the OAT structural gene is located on chromosome 10 and that there is a group of nonfunctional OAT-related sequences on the X chromosome.…”

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confidence: 95%

At least two mutant alleles of ornithine delta-aminotransferase cause gyrate atrophy of the choroid and retina in Finns.

Mitchell

Brody

Sipilä

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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Gyrate atrophy of the choroid and retina (GA) is an inherited chorioretinal degeneration caused by deficiency of ornithine 8-aminotransferase (OAT; L-ornithine: 2-oxo-acid aminotransferase; EC 2.6.1.13). GA is one of the "Finnish genetic diseases," a group of several rare monogenic disorders that occur with increased frequency in the Finnish population. Using a combination of RNase A protection, genomic cloning, and polymerase chain reaction amplification of genomic DNA, we found one of two missense mutant OAT alleles to be present in each of 16 Finnish GA pedigrees. The first mutation R180T, in which arginine-180 is replaced by threonine, was present in homozygous form in patients from two pedigrees. The second mutation L402P, in which leucine-402 is replaced by proline, was present in homozygous form in patients from 14 pedigrees. Neither mutation was present in 19 Finnish controls. L402P was not present in 18 non-Finnish GA patients but R180T was found in an American GA patient. We constructed full-length mutant cDNAs by amplifying patient cDNA with the polymerase chain reaction and cloning a restriction fragment containing the mutation into an otherwise normal human OAT cDNA. These mutant cDNAs were then expressed in CHO-K1 cells, which lack endogenous OAT. Both R180T and L402P inactivate OAT. These results show molecular heterogeneity in GA alleles even in the Finnish population.Ornithine 8-aminotransferase (OAT; L-ornithine:2-oxo-acid aminotransferase; EC 2.6.1.13) is a mitochondrial matrix enzyme that catalyzes the reversible transamination of ornithine to Al-pyrroline 5-carboxylate (1). Deficiency of OAT in man causes the autosomal recessive chorioretinal degeneration, gyrate atrophy of the choroid and retina (GA). To study the cell biology of OAT and the mutations causing GA, we have cloned and sequenced a near full-length human liver OAT cDNA and have determined the structure of the human OAT structural gene, which has 11 exons and spans 22 kilobases (kb) (2). We (2, 3) and others (4, 5) have shown that the OAT structural gene is located on chromosome 10 and that there is a group of nonfunctional OAT-related sequences on the X chromosome.Three missense mutations of OAT causing GA have been reported. The first mutation, in which the initiation methionine was replaced with an isoleucine, was found in affected members of two unrelated pedigrees of Lebanese Maronite descent (6). GA probands from 17 pedigrees of a variety of other ethnic backgrounds, including Finnish, were shown to lack this mutation (6). The second mutation was the Val-332 -* Met change found in a pyridoxine-responsive patient, and the third was the Asn-54 --Lys change (7). The ethnic background of the latter two patients was not provided.The Finnish population, which expanded from -250,000 in 1700 A.D. to -5 million at present, has been isolated genetically by geographical, linguistic, and cultural barriers (8). For these reasons, the variety and frequency of monogenic disorders in Finns is quite different from other European pop...

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confidence: 95%

At least two mutant alleles of ornithine delta-aminotransferase cause gyrate atrophy of the choroid and retina in Finns.

Mitchell

Brody

Sipilä

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

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“…(A) 2 kb of contiguous GPIIIa gene from exons 8 to 10 from the patient and her mother were engineered in frame into the OAT cDNA in the pcDNAI expression plasmid. Plasmids were transfected into K562 cells and the resulting transcripts analyzed 16 h later by RT-PCR using primers E5S (5Ј-GAGACTGCCTGTAAACTAGC-3Ј) and RA1, specific for OAT (60) and GPIIIa, respectively. In some constructs, position Ϫ6 to the splice donor site was mutated to G or A; similarly, position ϩ18 from the splice acceptor site was mutated from a C to an A.…”

Section: Discussionmentioning

confidence: 99%

Glanzmann thrombasthenia. Cooperation between sequence variants in cis during splice site selection.

Ying

Dietz²,

Montgomery

et al. 1996

J. Clin. Invest.

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Glanzmann thrombasthenia (GT), an autosomal recessive bleeding disorder, results from abnormalities in the platelet fibrinogen receptor, GPIIb-IIIa (integrin ␣ IIb ␤ 3 ). A patient with GT was identified as homozygous for a G → A mutation 6 bp upstream of the GPIIIa exon 9 splice donor site. Patient platelet GPIIIa transcripts lacked exon 9 despite normal DNA sequence in all of the cis -acting sequences known to regulate splice site selection. In vitro analysis of transcripts generated from mini-gene constructs demonstrated that exon skipping occurred only when the G → A mutation was cis to a polymorphism 116 bp upstream, providing precedence that two sequence variations in the same exon which do not alter consensus splice sites and do not generate missense or nonsense mutations, can affect splice site selection. The mutant transcript resulted from utilization of a cryptic splice acceptor site and returned the open reading frame. These data support the hypothesis that premRNA secondary structure and allelic sequence variants can influence splicing and provide new insight into the regulated control of RNA processing. In addition, haplotype analysis suggested that the patient has two identical copies of chromosome 17. Markers studied on three other chromosomes suggested this finding was not due to consanguinity.

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“…Intron primers were chosen so that the entire exon, including its splice junctions, could be analyzed. Furthermore, these intron sequences have no counterpart in OAT-related pseudogenes found on the X chromosome (4). Sequence analysis of the amplified fragment (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…As part of our study of OAT and its role in GA, we wished to define the OAT mutations causing GA. To this end we cloned a human liver OAT cDNA (2,3) and determined the organization of the human OAT structural gene (4). Multiple 1. Abbreviations used in this paper: GA, gyrate atrophy of the choroid and retina; OAT, ornithine-b-aminotransferase; PCR, polymerase chain reaction.…”

Section: Introductionmentioning

confidence: 99%

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An initiator codon mutation in ornithine-delta-aminotransferase causing gyrate atrophy of the choroid and retina.

et al. 1988

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Gyrate atrophy of the choroid and retina (GA) is an autosomal recessive chorioretinal degeneration caused by deficiency of the mitochondrial matrix enzyme, ornithine-5-aminotransferase (OAT). To study the molecular basis of the mutations causing GA, we cloned and sequenced the human OAT cDNA and determined the intron-exon arrangement of the structural gene. Using the cDNA template, we synthesized antisense RNA probes and performed RNase A protection experiments with RNA from four Lebanese GA patients. We found a probe-target mismatch at the 5' end of the first coding exon and amplified this region of the patients' genomic DNA using the polymerase chain reaction. Sequence analysis showed a G A transition, changing the initiator ATG (methionine) codon to ATA. This mutation segregates with the GA allele in both pedigrees. Initiation of translation at the closest in-frame methionine codon would truncate OAT by 138 amino acids, eliminating the entire mitochondrial leader sequence and 113 amino acids of the mature peptide.

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ORNITHINE AMINOTRANSFERASE (OAT): EVIDENCE FOR A DISPERSED GENE FAMILY WITH MEMBER(S) LOCALIZED TO Xp11.1 – Xp21.1

Cited by 5 publications

References 0 publications

At least two mutant alleles of ornithine delta-aminotransferase cause gyrate atrophy of the choroid and retina in Finns.

At least two mutant alleles of ornithine delta-aminotransferase cause gyrate atrophy of the choroid and retina in Finns.

Glanzmann thrombasthenia. Cooperation between sequence variants in cis during splice site selection.

An initiator codon mutation in ornithine-delta-aminotransferase causing gyrate atrophy of the choroid and retina.

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