Unusual clinical expression and long survival of a pseudouridylate synthase (PUS1) mutation into adulthood

Abstract

A homozygote missense mutation of the pseudouridylate synthase gene was found in an adult patient with chronic sideroblastic anemia, diarrhea, microcephaly and failure to thrive. Moderate muscle weakness occurred in adulthood (6-min walk distance at 26 years: 240 m, control range 380-782 m) but a profound deficiency of mitochondrial respiratory chain complexes I and IV were found in her skeletal muscle. This, to our knowledge, is the first example of long survival of this usually fatal mitochondrial deficiency into adulthood. We suggest giving consideration to mitochondrial translation deficiency in unexplained syndromic sideroblastic anemia in adulthood.

Mitochondrial DNA transcription and translation: clinical syndromes

“…A similar phenotype has been observed in mutations in YARS2 encoding the mitochondrial tyrosyl-tRNA synthetase [ 67 ]. Patients in consanguineous families of Persian, Jewish, and Italian origins presented with mental retardation, dysmorphic features, lactic acidosis, myopathy, sideroblastic anemia, and low activity of complexes 1 and 4 of the respiratory chain in muscles [ 53 , 54 , 68 ]. Some patients were reported with a mild phenotype of sideroblastic anemia and muscle weakness in adult age [ 54 , 69 ].…”

“…Patients in consanguineous families of Persian, Jewish, and Italian origins presented with mental retardation, dysmorphic features, lactic acidosis, myopathy, sideroblastic anemia, and low activity of complexes 1 and 4 of the respiratory chain in muscles [ 53 , 54 , 68 ]. Some patients were reported with a mild phenotype of sideroblastic anemia and muscle weakness in adult age [ 54 , 69 ]. A double localization of PUS1 has been demonstrated, the isoform localized to the nucleus is predicted to be shorter (isoform 2) than the mitochondrial isoform, which contains an N-terminal mitochondrial targetting sequence.…”

A Myopathy, Lactic Acidosis, Sideroblastic Anemia (Mlasa) Case Due to A Novel Pus1 Mutation

“…To date, eleven PUS1-mutated patients from six families have been described [ 2 , 5 , 6 , 7 , 8 ] and five mutations are reported. Ours is the first alteration allegedly causing a splicing aberration according to prediction by in silico analysis.…”

Myopathy, lactic acidosis and sideroblastic anemia 1 (MLASA1): A 25-year follow-up

“…Another less severely affected Italian patient was compound heterozygous for a frameshifting deletion and a missense pathogenic variant ( PUS1 c.487delA, p.Ile163Leufs*4 and c.884 G > A, p.Arg295Glu) [9]. The first Turkish patient was homozygous for a missense pathogenic variant ( PUS1 c.883C > T, p.Arg295Trp) while the second Turkish patient was homozygous for a different missense pathogenic variant ( PUS1 c.302A > G, p.Gln301Arg) [[10], [11]].…”