Cystathionine gamma-lyase: Clinical, metabolic, genetic, and structural studies.
We report studies of six individuals with marked elevations of cystathionine in plasma and/or urine. Studies of CTH, the gene that encodes cystathionine gamma-lyase, revealed the presence among these individuals of either homozygous or compound heterozygous forms of a novel large deletion, p.Gly57_Gln196del, two novel missense mutations, c.589C>T (p.Arg197Cys) and c.932C>T (p.Thr311Ile), and one previously reported alteration, c.200C>T (p.Thr67Ile). Another novel missense mutation, c.185G>T (p.Arg62His), was found in heterozygous form in three mildly hypercystathioninemic members of a Taiwanese family. In one severely hypercystathioninemic individual no CTH mutation was found. Brief clinical histories of the cystathioninemic/cystathioninuric patients are presented. Most of the novel mutations were expressed and the CTH activities of the mutant proteins determined. The crystal structure of the human enzyme, hCTH, and the evidence available as to the effects of the mutations in question, as well as those of the previously reported p.Gln240Glu, on protein structure, enzymatic activity, and responsiveness to vitamin B(6) administration are discussed. Among healthy Czech controls, 9.3% were homozygous for CTH c.1208G>T (p.Ser403Ile), previously found homozygously in 7.5% of Canadians for whom plasma total homocysteine (tHcy) had been measured. Compared to wild-type homozygotes, among the 55 Czech c.1208G>T (p.Ser403Ile) homozygotes a greater level of plasma cystathionine was found only after methionine loading. Three of the four individuals homozygous or compound heterozygous for inactivating CTH mutations had mild plasma tHcy elevations, perhaps indicating a cause-and-effect relationship. The experience with the present patients provides no evidence that severe loss of CTH activity is accompanied by adverse clinical effects.
Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.
Jan P
JP
Kraus
Jindrich
J
Hasek
Viktor
V
Kozich
Renata
R
Collard
Sarah
S
Venezia
Bohumila
B
Janosíková
Jian
J
Wang
Sally P
SP
Stabler
Robert H
RH
Allen
Cornelis
C
Jakobs
Christine T
CT
Finn
Yin-Hsiu
YH
Chien
Wuh-Liang
WL
Hwu
Robert A
RA
Hegele
S Harvey
SH
Mudd
D000328:Adult; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics; D020134:Catalytic Domain; D002675:Child, Preschool; D003540:Cystathionine / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000235:genetics* / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense
D003540:Cystathionine; D003542:Cystathionine gamma-Lyase