Identical germ-line mutations in the triosephosphate isomerase alleles of two brothers are associated with distinct clinical phenotypes

Valentin, Colette; Cohen-Solal, M.; Maquat, Lynne E.; Horányi, Margit; Inselt-Kovács, Marianne; Hollán, Susan R.

doi:10.1016/s0764-4469(00)00128-1

Cited by 10 publications

(8 citation statements)

References 17 publications

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“…The mutations result in severely decreased TPI activity, however, only the younger sibling (affected brother) manifests a neurologic disorder. The entire genomic TPI locus (exons, introns and promoter) was sequenced and found to be identical in the two compound heterozygote brothers (7,29). Both brothers have the same well-compensated level of nonspherocytic hemolytic anemia and both the heterozygous mother and father are symptom-free (Table 2).…”

Section: Unique Characteristics Of Tpi Deficiency In a Hungarian Familymentioning

confidence: 99%

Triosephosphate isomerase deficiency: Facts and doubts

Orosz

Oláh

Ovádi

2006

TBMB

106

111

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SummaryMany glycolytic enzymopathies have been described that manifest clinically as chronic hemolytic anemia. One of these, triosephosphate isomerase (TPI) deficiency, is unique among the glycolytic enzyme defects since it is associated with progressive neurological dysfunction and frequently with childhood death. The physiological function of TPI is to adjust the rapid equilibrium between dihydroxyacetone phosphate and glyceraldehyde-3-phosphate produced by aldolase in glycolysis, which is interconnected to the pentose phosphate pathway and to lipid metabolism via triosephosphates. The TPI gene is well characterized; structure and function studies suggest that instability of the isomerase due to different mutations of the enzyme may underlie the observed reduced catalytic activity. Patients with various inherited mutations have been identified. The most abundant mutation is a Glu104Asp missense mutation that is found in homozygotes and compound heterozygotes. Two germ-line identical Hungarian compound heterozygote brothers with distinct phenotypes question the exclusive role of the inherited mutations in the etiology of neurodegeneration. This paper: (i) reviews our present understanding of TPI mutation-induced structural alterations and their pathological consequences, (ii) summarizes the consequences of TPI impairment in the Hungarian case at local and system levels, and (iii) raises critical questions regarding the exclusive role of TPI mutations in the development of this human disease.

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Section: Unique Characteristics Of Tpi Deficiency In a Hungarian Familymentioning

confidence: 99%

Triosephosphate isomerase deficiency: Facts and doubts

Orosz

Oláh

Ovádi

2006

TBMB

106

111

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“…3,4 The metabolic block in glycolysis results in very high level of DHAP as determined in red blood cells (RBCs). 4 Two compound heterozygote Hungarian brothers (both beyond 20 years) with TPI activity less than 5% 5 inherited 2 separate mutations: Phe240Leu 6 and Glu145stop codon 7 from their mother and from their father, respectively. The propositus, the younger brother, has chronic hemolytic anemia and extrapyramidal neurodegeneration.…”

Section: Introductionmentioning

confidence: 99%

Distinct behavior of mutant triosephosphate isomerase in hemolysate and in isolated form: molecular basis of enzyme deficiency

Orosz

Oláh

Alvarez

et al. 2001

Blood

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In a Hungarian family with severe decrease in triosephosphate isomerase (TPI) activity, 2 germ line-identical but phenotypically differing compound heterozygote brothers inherited 2 independent (Phe240Leu and Glu145stop codon) mutations. The kinetic, thermodynamic, and associative properties of the recombinant human wild-type and Phe240Leu mutant enzymes were compared with those of TPIs in normal and deficient erythrocyte hemolysates. The specific activity of the recombinant mutant enzyme relative to the wild type was much higher (30%) than expected from the activity (3%) measured in hemolysates.

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“…Inhibition of TPI activity by Abs has been reported in hepatitis A virus infections (40). Moreover, patients with TPI deficiency develop progressive neurological disorders (30).…”

Section: Downloaded Frommentioning

confidence: 98%

Triosephosphate Isomerase- and Glyceraldehyde-3-Phosphate Dehydrogenase-Reactive Autoantibodies in the Cerebrospinal Fluid of Patients with Multiple Sclerosis

Kölln¹,

Ren²,

Da³

et al. 2006

The Journal of Immunology

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Our previous results revealed that Igs in lesions and single chain variable fragment Abs (scFv-Abs) generated from clonal B cells in the cerebrospinal fluid (CSF) from patients with multiple sclerosis (MS) bind to axons in MS brains. To study the axonal Ags involved in MS, we identified the glycolytic enzymes, triosephosphate isomerase (TPI) and GAPDH, using Igs from the CSF and scFv-Abs generated from clonal B cells in the CSF and in lesions from MS patients. Elevated levels of CSF-Abs to TPI were observed in patients with MS (46%), clinically isolated syndrome (CIS) suggestive of MS (40%), other inflammatory neurological diseases (OIND; 29%), and other noninflammatory neurological diseases (ONIND; 31%). Levels of GAPDH-reactive Abs were elevated in MS patients (60%), in patients with CIS (10%), OIND (14%), and ONIND (8%). The coexistence of both autoantibodies was detected in 10 MS patients (29%), and 1 CIS patient (3%), but not in patients with OIND/ONIND. Two scFv-Abs generated from the CSF and from lesions of a MS brain showed immunoreactivity to TPI and GAPDH, respectively. The findings suggest that TPI and GAPDH may be candidate Ags for an autoimmune response to neurons and axons in MS.

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Identical germ-line mutations in the triosephosphate isomerase alleles of two brothers are associated with distinct clinical phenotypes

Cited by 10 publications

References 17 publications

Triosephosphate isomerase deficiency: Facts and doubts

Triosephosphate isomerase deficiency: Facts and doubts

Distinct behavior of mutant triosephosphate isomerase in hemolysate and in isolated form: molecular basis of enzyme deficiency

Triosephosphate Isomerase- and Glyceraldehyde-3-Phosphate Dehydrogenase-Reactive Autoantibodies in the Cerebrospinal Fluid of Patients with Multiple Sclerosis

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