Inherited thrombocytopenia associated with mutation of UDP-galactose-4-epimerase (GALE)

Abstract

Severe thrombocytopenia, characterized by dysplastic megakaryocytes and intracranial bleeding, was diagnosed in six individuals from a consanguineous kindred. Three of the individuals were successfully treated by bone marrow transplant. Whole-exome sequencing and homozygosity mapping of multiple family members, coupled with whole-genome sequencing to reveal shared non-coding variants, revealed one potentially functional variant segregating with thrombocytopenia under a recessive model: GALE p.R51W (c.C151T, NM_001127621). The mutation is extremely rare (allele frequency = 2.5 × 10−05), and the likelihood of the observed co-segregation occurring by chance is 1.2 × 10−06. GALE encodes UDP-galactose-4-epimerase, an enzyme of galactose metabolism and glycosylation responsible for two reversible reactions: interconversion of UDP-galactose with UDP-glucose and interconversion of UDP-N-acetylgalactosamine with UDP-N-acetylglucosamine. The mutation alters an amino acid residue that is conserved from yeast to humans. The variant protein has both significantly lower enzymatic activity for both interconversion reactions and highly significant thermal instability. Proper glycosylation is critical to normal hematopoiesis, in particular to megakaryocyte and platelet development, as reflected in the presence of thrombocytopenia in the context of congenital disorders of glycosylation. Mutations in GALE have not previously been associated with thrombocytopenia. Our results suggest that GALE p.R51W is inadequate for normal glycosylation and thereby may impair megakaryocyte and platelet development. If other mutations in GALE are shown to have similar consequences, this gene may be proven to play a critical role in hematopoiesis.

Inherited thrombocytopenias: history, advances and perspectives

“…In a separate study, severe thrombocytopenia with enlarged platelets and dysplastic megakaryocytes was the characteristic of six members of a consanguineous family in whom WES and homozygosity mapping revealed a homozygous mutation in GALE, encoding UDP-galactose-4-epimerase, an enzyme responsible for UDP-galactose inter-conversion with UDP-glucose and UDP-N-acetylgalactosamine inter-conversion with UDP-N-acetylglucosamine. 112 Some individuals also showed mild anemia and febrile neutropenia while galactosemia is a feature of mutations of this gene. With predicted protein instability, the enzyme retained 40% of its normal activity.…”

Inherited Thrombocytopenia: Update on Genes and Genetic Variants Which may be Associated With Bleeding

“…Since the last decade, next generation sequencing technologies, namely Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS) coupled with conventional Sanger sequencing and in-silico bioinformatic tools have been used in parallel to uncover novel genes with a pivotal role in megakaryocyte biology and platelet biogenesis (10, 11). To date, 40 genes have been reported to cause different forms of IT, which reflects the immense difficulty in identifying a single causative gene, particularly when accompanied by other hematological disorders [Table 1; Figure 1; (27, 28, 54)]. These genetic forms have various clinical manifestations, phenotypic presentations and sometimes associated with secondary qualitative defects in platelet function (7).…”

β4GALT1 controls β1 integrin function to govern thrombopoiesis and hematopoietic stem cell homeostasis

“…Genetic alterations responsible for sialic acid and galactose (Gal) metabolism in humans regulate circulating platelet count, specifically in patients with mutations in GALE and GNE [18][19][20] . In mice, sialylated derivatives of the glycan structure β1,4-N-acetyllactosamine (Galβ1,4-GlcNAc or type-2 LacNAc, hereafter referred to as LacNAc), regulate platelet lifespan, hepatic thrombopoietin (TPO) production, and thus HSCs and thrombopoiesis 21,22 .…”