Mutation of the fumarase gene in two siblings with progressive encephalopathy and fumarase deficiency.

Abstract

We report an inborn error of the tricarboxylic acid cycle, fumarase deficiency, in two siblings born to first cousin parents. They presented with progressive encephalopathy, dystonia, leucopenia, and neutropenia. Elevation of lactate in the cerebrospinal fluid and high fumarate excretion in the urine led us to investigate the activities of the respiratory chain and of the Krebs cycle, and to finally identify fumarase deficiency in these two children. The deficiency was profound and present in all tissues investigated, affecting the cytosolic and the mitochondrial fumarase isoenzymes to the same degree. Analysis of fumarase cDNA demonstrated that both patients were homozygous for a missense mutation, a G-955 -> C transversion, predicting a Glu-319 --Gln substitution. This substitution occurred in a highly conserved region of the fumarase cDNA. Both parents exhibited half the expected fumarase activity in their lymphocytes and were found to be heterozygous for this substitution. The present study is to our knowledge the first molecular characterization of tricarboxylic acid deficiency, a rare inherited inborn error of metabolism in childhood.

Downregulation of SRF–FOS–JUNB pathway in fumarate hydratase deficiency and in uterine leiomyomas

“…In short, four FH-deficient fibroblast lines from patients with recessive FH deficiency were used-FH-1, homozygous for the E362Q mutation (Bourgeron et al, 1994); FH-2, homozygous for the Q376P mutation (Remes et al, 2004); FH-3 is a compound heterozygote with InsK477/ R233H (Loeffen et al, 2005); and FH-4 is a compound heterozygote with delV387 and Q386H changes in one allele, and P369S in the other (Maradin et al, 2006). (These lines were kind gifts from Pierre Rustin (Bourgeron et al, 1994), Jan Smeitink (Loeffen et al, 2005), Anne M Remes (Remes et al, 2004) and Ksenija Fumic´, Ivo Baric´ (Maradin et al, 2006).) The residual FH activities in these lines were o1% for FH-1, o0.5% for FH-2, 20% for FH-3 and 5% for FH-4 (Bourgeron et al, 1994;Remes et al, 2004;Loeffen et al, 2005;Maradin et al, 2006).…”

Fumarase Deficiency in Dichorionic Diamniotic Twins

“…The FH gene on chromosome 1q42 encodes two isoenzymes, one in the cytosol and the other in the mitochondrial matrix (Bourgeron et al, 1994).…”

Missense Mutations in Fumarate Hydratase in Multiple Cutaneous and Uterine Leiomyomatosis and Renal Cell Cancer

“…Here we show that FH missense mutations significantly occurred in fully conserved residues and in residues functioning in the FH A-site, B-site, or subunit-interacting region. Of 24 distinct missense mutations, 13 In the autosomal dominant syndrome of multiple cutaneous and uterine leiomyomatosis (MCUL, Reed syndrome, leiomyomatosis cutis et uteri, multiple leiomyomatosis; OMIM 150800), affected females develop uterine leiomyomas and affected individuals of both sexes develop cutaneous leiomyomas. 1 Cutaneous leiomyomas are believed to be derived from the smooth muscle of the pilo-arrector apparatus.…”

“…Clinical features of FHD include progressive encephalopathy, developmental delay, hypotonia, cerebral malformation and atrophy, and lactic and pyruvic acidemia with death usually occurring in infancy or by the first decade. [12][13][14][15] Thus this is an uncommon example of a situation in which heterozygous and homozygous mutations of a single gene give rise to very different phenotypes. The germline mutations of 11 FHD patients have been reported (Table 4).…”

“…5,[12][13][14][15] In all of these cases, and in some patients who have not had mutation screening, affected individuals have been shown to have low FH activity, ranging from Ͻ1 to 20% of that of controls. 5,[12][13][14][15] Two missense mutations, R190H and K187R, have been reported in both MCUL/HLRCC and FHD and MCUL/FHD, respectively. 5 In this study, we also examined features of the missense FH mutations reported in FHD.…”