Prenatal diagnosis and fetal pathology in a Turkish family harboring a novel nonsense mutation in the lysosomal α-N-acetyl-neuraminidase (sialidase) gene

Abstract

We report a Turkish family with parental consanguinity and at risk for sialidosis type II, an inherited autosomal recessive disorder caused by lysosomal alpha-N-acetyl-neuraminidase (sialidase, NEU1) deficiency. The proband was a premature male infant that presented with hydrops, hepatomegaly, respiratory distress syndrome, and anemia and that died of respiratory insufficiency 2 months after birth despite intensive care. An abnormally increased [14C]methylamine incorporation and an isolated deficiency of lysosomal alpha-N-acetyl-neuraminidase were found in cultured skin fibroblasts. A previous pregnancy of the mother terminated in a spontaneous abortion in the 13th week of gestation. A successive pregnancy showed hydrops fetalis, and an enzymatic assay of cultured amniotic fluid cells indicated a deficiency of alpha-N-acetyl-neuraminidase. Following pregnancy termination at 20 weeks gestation, light microscopy of fetal tissues revealed classic vacuolation not only in liver, bone marrow, brain, and kidney, but also in endocrine organs such as the thyroid gland, adrenal gland, hypophysis, and testes, and in the thymus. DNA analysis of the family showed that both the proband and the third sibling had a novel homozygous nonsense point mutation at nucleotide 87 in exon 1 of the alpha-N-acetyl-neuraminidase (neu1) gene causing a substitution of tryptophan at codon 29 by a termination codon (W29X). DNA sequencing of polymerase chain reaction products identified the parents as heterozygous carriers. To detect neu1 mRNA expression, a real-time reverse transcription/polymerase chain reaction was performed, and similar rates of neu1 mRNA expression were found in the fibroblasts of the fetus, the 2nd sibling, and in controls. The very early termination codon with complete loss of neuraminidase activity is probably the molecular basis of the unusually severe vacuolation pattern in this form of congenital sialidosis.

Impact of β-galactosidase mutations on the expression of the canine lysosomal multienzyme complex

“…These results are in concordance with the observation that some human GLB1 mutant alleles are not associated with modifications in NEU1 expression [10]. A lack of variation in the NEU1 expression was also described when sialidosis patients (NEU1 -/-) were compared to control healthy individuals (NEU1 +/+ ) [46].…”

Molecular pathology of NEU1 gene in sialidosis

“…Three nonsense mutations have been reported: c.838C>T (p.R280X), c.1129G>T (p.E377X) 1 [Bonten et al, 2000], and c.87G>A (p.W29X) [Sergi et al, 2001]. All of them should result in a synthesis of truncated proteins without catalytic activity.…”

“…Siblings carrying this mutation in one allele showed a mild clinical phenotype because of the V54M missense mutation in the other allele that reduced enzymatic activity of the mutant sialidase in vitro to only~40% of the normal level [Bonten et al, 2000]. R280X and W29X mutations were found in the most severely affected patients with a congenital form of sialidosis [Bonten et al, 2000;Sergi et al, 2001].…”

Clinical and Serial MRI Findings of a Sialidosis Type I Patient with a Novel Missense Mutation in the <i>NEU1</i> Gene

“…The age of onset and severity of the clinical manifestations are correlated with NEU1 mutations (10,11) and the level of residual neuraminidase activity (10,12,13), indicating the existence of considerable genotype-phenotype correlation in this disease. To date, more than 40 mutations within the NEU1 gene have been identified in patients with sialidosis type I or type II (2,3,(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24).…”