Barbara Triggs-Raine

University of Manitoba | UMN · Department of Biochemistry and Medical Genetics

Hyaluronan (HA) is a large polysaccharide that is broadly distributed and highly abundant in the soft connective tissues and embryos of vertebrates. The constitutive turnover of HA is very high, estimated at 5 g per day in an average (70 kg) adult human, but HA turnover must also be tightly regulated in some processes. Six genes encoding homologues...

Silver-Russell syndrome (SRS) is a heterogeneous disorder characterized by intrauterine and postnatal growth retardation. HMGA2 variants are a rare cause of SRS and its functional role in human linear growth is unclear. Patients with suspected SRS negative for 11p15LOM/mUPD7 underwent whole-exome and/or targeted-genome sequencing. Mutant HMGA2 prot...

Silver-Russell syndrome (SRS) is a heterogeneous disorder characterized by intrauterine and postnatal growth retardation. HMGA2 variants are a rare cause of SRS and its functional role in human linear growth is unclear. Patients with suspected SRS negative for 11p15LOM/mUPD7 underwent whole-exome and/or targeted-genome sequencing. Mutant HMGA2 prot...

Mitochondrial quality control is critical in muscle to ensure both contractile and metabolic function. Nix is a BCL-2 family member, mitophagy receptor, and has recently been implicated in muscle atrophy. Human GWAS suggests altered Nix expression could predispose individuals to manifestations of mitochondrial disease. To interrogate the role of Ni...

Over the past several years, I have been interacting with an increasing number of Iranian scientists, including those currently living in Iran as well as others who are being educated elsewhere or have independent positions outside of that country. In all circumstances, the resulting collaborations have extended my own knowledge and allowed me to c...

The mucopolysaccharidoses (MPSs) are a group of lysosomal diseases, each characterized by a specific enzyme deficiency related to a specific gene defect that affects one of the steps of the stepwise degradation pathway of glycosaminoglycans, leading to progressive storage of these compounds in tissues and organs. These diseases are genetically very...

Tay-Sachs and Sandhoff diseases are genetic disorders resulting from mutations in HEXA or HEXB, which code for the α- and β-subunits of the heterodimer β-hexosaminidase A (HexA), respectively. Loss of HexA activity results in the accumulation of GM2 ganglioside (GM2) in neuronal lysosomes, culminating in neurodegeneration and death, often by age 4....

Purpose We previously defined biallelic HYAL2 variants causing a novel disorder in 2 families, involving orofacial clefting, facial dysmorphism, congenital heart disease, and ocular abnormalities, with Hyal2 knockout mice displaying similar phenotypes. In this study, we better define the phenotype and pathologic disease mechanism. Methods Clinical...

Prolactin-inducible protein (PIP) is a multifunctional glycoprotein that is highly expressed and found in the secretions of apocrine glands such as salivary, lacrimal, and sweat glands including the mammary glands. PIP has been implicated in various diseases, including breast cancer, gross cystic disease of the breast, keratoconus of the eye, and t...

Host‐pathogen interactions play an important role in defining the outcome of a disease. Recent studies have shown that the bacterial quorum sensing molecules (QSM) can interact with host cell membrane proteins, mainly G protein‐coupled receptors (GPCRs), and induce innate immune responses. However, few studies have examined QSM‐GPCR interactions an...

Chronic hypoxia leads to pathologic remodeling of the pulmonary vasculature and pulmonary hypertension (PH). The antioxidant enzyme extracellular superoxide dismutase (SOD3) protects against hypoxia-induced PH. Hyaluronan (HA), a ubiquitous glycosaminoglycan of the lung extracellular matrix, is rapidly recycled at sites of vessel injury and repair....

The glycosylphosphatidylinositol‐anchored sperm hyaluronidases (Hyals), sperm adhesion molecule 1 (SPAM1) and HYAL5, have long been believed to assist in sperm penetration through the cumulus‐oocyte complex (COC), but their role in mammalian fertilization remains unclear. Previously, we have shown that mouse sperm devoid of either Spam1 or Hyal5 ar...

Background and aims: Phytosterolemia is a rare genetic disease caused by mutation of the ABCG5/8 gene. Our aim was to elucidate the natural history and homeostasis of phytosterolemia. Methods: We analyzed a Hutterite kindred consisting of 21 homozygotes with phytosterolemia assembled over a period of two decades, all of whom carried the ABCG8 S1...

Background— Hyaluronan (HA) is required for endothelial-to-mesenchymal transition and normal heart development in the mouse. Heart abnormalities in hyaluronidase 2 (HYAL2)–deficient (Hyal2⁻/−) mice and humans suggested removal of HA is also important for normal heart development. We have performed longitudinal studies of heart structure and functio...

Orofacial clefting is amongst the most common of birth defects, with both genetic and environmental components. Although numerous studies have been undertaken to investigate the complexities of the genetic etiology of this heterogeneous condition, this factor remains incompletely understood. Here, we describe mutations in the HYAL2 gene as a cause...

Background Primary immunodeficiency is a life-threatening genetic disease that appeared to have an increased incidence in Manitoba Mennonites. Determining the genetic basis of this immunodeficiency was an essential step for providing early and appropriate medical intervention. Methods Initially, DNA from probands affected with primary immunodefici...

Background: The Hutterites are a religious isolate living in colonies across the North American prairies. This population originated from approximately 90 founders, resulting in a number of genetic diseases that are overrepresented, underrepresented, or unique. The founder effect in this population increases the likelihood that Hutterite couples c...

Hyaluronidase 2 (HYAL2) is a membrane-anchored protein that is proposed to initiate the degradation of hyaluronan (HA) in the extracellular matrix. The distribution of HYAL2 in tissues, and of HA in tissues lacking HYAL2, is largely unexplored despite the importance of HA metabolism in several disease processes. Herein, we use immunoblot and histoc...

Hyaluronidase 2 (HYAL2) is a membrane-anchored protein that is proposed to initiate the degradation of hyaluronan (HA) in the extracellular matrix. The distribution of HYAL2 in tissues, and of HA in tissues lacking HYAL2, is largely unexplored despite the importance of HA metabolism in several disease processes. Herein, we use immunoblot and histoc...

Hyaluronan is a rapidly turned over component of the vertebrate extracellular matrix. Its levels are determined, in part, by the hyaluronan synthases, HAS1, HAS2, and HAS3, and three hyaluronidases, HYAL1, HYAL2 and HYAL3. Hyaluronan binding proteins also regulate hyaluronan levels although their involvement is less well understood. To date, two ge...

Hyaluronan is a rapidly turned over component of the vertebrate extracellular matrix. Its levels are determined, in part, by the hyaluronan synthases, HAS1, HAS2, and HAS3, and three hyaluronidases, HYAL1, HYAL2 and HYAL3. Hyaluronan binding proteins also regulate hyaluronan levels although their involvement is less well understood. To date, two ge...

Nonsense-mediated mRNA decay (NMD), an mRNA surveillance mechanism, eliminates premature termination codon-containing (PTC(+)) transcripts. For instance, it maintains the homeostasis of splicing factors and degrades aberrant transcripts of human genetic disease genes. Here we have found that several PTC(+) transcripts including that of serine/argin...

Bowen-Conradi syndrome (BCS) is a ribosomopathy characterized by severe developmental delay and growth failure that typically leads to death by one year of age. It is caused by a c.257A>G p.D86G substitution in the ribosomal biogenesis protein, Essential for Mitotic Growth 1 (EMG1). We generated a knock-in of the D86G substitution in mice to charac...

GM2 gangliosidoses are severe neurodegenerative disorders resulting from a deficiency in ß-hexosaminidase A activity and lacking effective therapies. Using a Sandhoff disease (SD) mouse model (Hexb(-/-)) of the GM2 gangliosidoses, we tested the potential of systemically delivered adeno-associated virus (AAV) 9 expressing Hexb cDNA to correct the ne...

Bowen–Conradi syndrome (BCS) is a lethal autosomal recessive disorder caused by a D86G substitution in the protein, Essential for Mitotic Growth 1 (EMG1). EMG1 is essential for 18S rRNA maturation and 40S ribosome biogenesis in yeast, but no studies of its role in ribosome biogenesis have been done in mammals. To assess the effect of the EMG1 mutat...

Collectively, the ribosomopathies are caused by defects in ribosome biogenesis. Although these disorders encompass deficiencies in a ubiquitous and fundamental process, the clinical manifestations are extremely variable and typically display tissue specificity. Research into this paradox has offered fascinating new insights into the role of the rib...

Bowen-Conradi syndrome (BCS), a lethal autosomal recessive disorder which affects infants in the Hutterite population, is caused by a point mutation in EMG1, a highly conserved gene necessary for biogenesis of the small subunit of the ribosome. Research on EMG1 function has centered on yeast models, due to their genetic tractability for examining a...

Hyaluronidase 2 (HYAL2) is a membrane-anchored protein that is proposed to hydrolyze hyaluronan (HA) to smaller fragments that are internalized for breakdown. Initial studies of a Hyal2 knockout (KO) mouse revealed a mild phenotype with high serum HA, supporting a role for HYAL2 in HA breakdown. We now describe a severe cardiac phenotype, deemed ac...

Mutations of the glycogen branching enzyme gene, GBE1, result in glycogen storage disease (GSD) type IV, an autosomal recessive disorder having multiple clinical forms. One mutant allele of this gene, GBE1 c.1076A>C, has been reported in Ashkenazi Jewish cases of an adult-onset form of GSD type IV, adult polyglucosan body disease (APBD), but no epi...

Autosomal-recessive inheritance, severe to profound sensorineural hearing loss, and partial agenesis of the corpus callosum are hallmarks of the clinically well-established Chudley-McCullough syndrome (CMS). Although not always reported in the literature, frontal polymicrogyria and gray matter heterotopia are uniformly present, whereas cerebellar d...

Ovarian follicle development is a process regulated by various endocrine, paracrine and autocrine factors that act coordinately to promote follicle growth. However, the vast majority of follicles does not reach the pre-ovulatory stage but instead, undergo atresia by apoptosis. We have recently described a role for the somatic hyaluronidases (Hyal-1...

Hyaluronan (HA), a member of the glycosaminoglycan (GAG) family, is a critical component of the extracellular matrix. A model for HA degradation that invokes the activity of both hyaluronidases and exoglycosidases has been advanced. However, no in vivo studies have been done to determine the extent to which these enzymes contribute to HA breakdown....

Plant sterol (PS) supplementation is increasingly accepted as a dietary strategy to lower plasma cholesterol concentrations. However, information is scarce about the effect of increased PS intake in potentially vulnerable groups, such as phytosterolemia heterozygotes (HET). This study assessed the responsiveness of circulating PS and lipid concentr...

We describe a single consanguineous family with three affected children exhibiting knee and/or hip pain associated with swelling. Detailed clinical evaluation demonstrated diffuse joint involvement with an unusual proliferative synovitis on MRI. Synovial biopsies were notable for an infiltration of macrophages with abundant cytoplasm filled with fa...

Hydroperoxidase I (HPI) of Escherichia coli is a bifunctional enzyme exhibiting both catalase and peroxidase activities. Mutants lacking appreciable HPI have been generated using nitrosoguanidine and the gene encoding HPI, katG, has been cloned from three of these mutants using either classical probing methods or polymerase chain reaction amplifica...

p53 inactivation fails to rescue the pre-implantation arrest of the Emg1 null allele. E3.5 embryos were collected from intercross of Emg1+/-/p53+/- (A) and cross of Emg1+/-/p53-/-(male) with Emg1+/-/p53+/- (female) (B). In both, Emg1-/-/p53-/- embryos show the same morula arrest as Emg-/-/p53+/- or Emg-/-embryos. Scale bar, 100μm.

Expression of NANOG in Emg1-/- mutant embryos. E3.5 embryos from Emg1+/- intercross were co-immunostained with anti-NANOG (red) and anti-β-catenin (green) antibodies. In E3.5 Emg1+/+ blastocysts, nuclear-localized NANOG is mainly found in the ICM. NANOG is also detected in the blastomeres of E2.5 Emg1+/+ morulae. At E3.5, Emg1-/- embryos arrest at...

Essential for mitotic growth 1 (EMG1) is a highly conserved nucleolar protein identified in yeast to have a critical function in ribosome biogenesis. A mutation in the human EMG1 homolog causes Bowen-Conradi syndrome (BCS), a developmental disorder characterized by severe growth failure and psychomotor retardation leading to death in early childhoo...

The molecular mechanisms underlying sperm penetration of the physical barriers surrounding the oocyte have not been completely delineated. Although neutral-active or "reproductive" hyaluronidases (hyases), exemplified by Sperm Adhesion Molecule 1 (SPAM1), are thought to be responsible for hyaluronan digestion in the egg vestments and for sperm-zona...

Mammalian hyaluronidases degrade hyaluronan and some structurally related glycosaminoglycans. We generated a deletion mutant in the Caenorhabditis elegans orthologue of mammalian hyaluronidase, hya-1. Mutant animals are viable and grossly normal, but exhibit defects in vulval morphogenesis and egg-laying and showed increased staining with alcian bl...

Hyaluronidase 2 (Hyal2) is a GPI-linked endoglycosidase thought to initiate the degradation of hyaluronan (HA). HA is an abundant component of the extracellular matrix where it has an important role in matrix assembly, wound healing and embryonic development. Our objective was to characterize the cardiac abnormalities detected in Hyal2 knock-out (K...

Hyaluronidase 2 (Hyal2) is a GPI‐linked endoglycosidase thought to initiate the degradation of hyaluronan (HA). HA is an abundant component of the extracellular matrix where it has an important role in matrix assembly, wound healing and embryonic development. Our objective was to characterize the cardiac abnormalities detected in Hyal2 knock‐out (K...

Mammalian hyaluronidases (EC 3.2.1.35) are endo-β-N-acetyl-hexosaminidases, that hydrolyze hyaluronic acid (hyaluronan), and to a lesser extent chondroitin and chondroitin sulfate, to generate mostly tetra-saccharides. In the ovary, expression of three hyaluronidases (Hyal-1, Hyal-2 and Hyal-3) has been documented and our group has recently shown t...

Bowen-Conradi syndrome (BCS) is an autosomal-recessive disorder characterized by severely impaired prenatal and postnatal growth, profound psychomotor retardation, and death in early childhood. Nearly all reported BCS cases have been among Hutterites, with an estimated birth prevalence of 1/355. We previously localized the BCS gene to a 1.9 Mbp int...

The metabolism of hyaluronan (HA) relies on HA synthases and hyaluronidases, among which hyaluronidase-1 (HYAL1) and -2 (HYAL2) have been proposed as key actors. Congenital HYAL1 deficiency leads to mucopolysaccharidosis IX (MPS IX), a rare lysosomal storage disorder characterized by joint abnormalities. Knowledge of HYAL2 is limited. This protein...

Hyaluronidases are endoglycosidases that initiate the breakdown of hyaluronan (HA), an abundant component of the vertebrate extracellular matrix. In humans, six paralogous genes encoding hyaluronidase-like sequences have been identified on human chromosomes 3p21.3 (HYAL2-HYAL1-HYAL3) and 7q31.3 (SPAM1-HYAL4-HYALP1). Mutations in one of these genes,...

Hyaluronidases are endoglycosidases that hydrolyze hyaluronan (HA), an abundant component of the extracellular matrix of vertebrate connective tissues. Six human hyaluronidase-related genes have been identified to date. Mutations in one of these genes cause a deficiency of hyaluronidase 1 (HYAL1) resulting in a lysosomal storage disorder, mucopolys...

Hyaluronidases are endoglycosidases that hydrolyze hyaluronan (HA), an abundant component of the extra- cellular matrix of vertebrate connective tissues. Six human hyaluronidase-related genes have been identified to date. Mutations in one of these genes cause a deficiency of hyaluronidase 1 (HYAL1) resulting in a lyso- somal storage disorder, mucop...

Hyaluronidases are enzymes that mediate the breakdown of hyaluronan (HA), a large polysaccharide abundant in the extracellular matrix of vertebrate tissues. Six genes have been predicted to encode hyaluronidases in humans, but the protein products of only SPAM1, HYAL1, and HYAL2 have been characterized. We have now expressed the mouse Hyal3 gene pr...

The assessment of risk for Tay-Sachs disease (TSD) in individuals of French Canadian background living in New England is an important health issue. In preliminary studies of the enzyme-defined carrier frequency for TSD among Franco-Americans in New England, we found frequencies (1:53) higher than predicted from the incidence of infantile TSD in thi...

The tetrameric glycoprotein butyrylcholinesterase (BChE; EC 3.1.1.8) is one of two enzymes that hydrolyze choline esters. The controlling gene (BCHE) is comprised of four coding exons and is located on chromosome 3q26. Based on BChE activity measurements in the presence and absence of dibucaine, usual (designated U) and atypical (designated A) gene...

Bowen-Conradi syndrome (BCS) is a lethal autosomal recessive disorder with an estimated incidence of 1 in 355 live births in the Hutterite population. A few cases have been reported in other populations. Here, we report the results of a genome-wide scan and fine mapping of the BCS locus in Hutterite families. By linkage and haplotype analysis the B...

We have characterized the molecular basis of beta-hexosaminidase A (HEX A) deficiency in a patient ascertained through an ophthalmologic examination that revealed cherry red spots on his retina. The absence of neurological deficit in this child until 3 3/4 years of age indicated residual HEX A must be present. Three HEXA mutations, 10T > C (S4P) an...

To investigate the prevalence of the unique HNF-1alpha G319S mutation in a population of aboriginal youth with type 2 diabetes and to describe the relationship between clinical and historical characteristics and the presence or absence of the HNF-1alpha G319S mutation. Participating youth were genotyped for the G319S mutation of the HNF-1alpha gene...

Hyaluronidases are required for the breakdown of hyaluronan (HA), an abundant component of the extracellular matrix of vertebrate tissues. Multiple hyaluronidase genes have been identified, but the only clue to the function of their products has come from the identification of hyaluronidase 1 deficiency in a single patient with a mild clinical phen...

The prevalence of type 2 diabetes mellitus in the Oji-Cree of northwestern Ontario is the third highest in the world. A private mutation, G319S, in HNF1A, which encodes hepatic nuclear factor-1alpha (HNF-1alpha), was associated with Oji-Cree type 2 diabetes and was found in approximately 40% of affected subjects. The G319S mutation reduced the in v...

β-Hexosaminidase, a family 20 glycosyl hydrolase, catalyzes the removal of β-1,4-linkedN-acetylhexosamine residues from oligosaccharides and their conjugates. Heritable deficiency of this enzyme results in various forms of GalNAc-β(1,4)-[N-acetylneuraminic acid (2,3)]-Gal-β(1,4)-Glc-ceramide gangliosidosis, including Tay-Sachs disease. We have dete...

To identify proteins interacting in the insulin-signaling pathway that might define new pathways or regulate existing ones, we have employed the yeast two-hybrid system. In a two-hybrid screen of a human liver cDNA library, we identified the human growth factor receptor bound 14 (hGrb14) adaptor protein as a partner of the activated insulin recepto...

Hyaluronan (HA), a large glycosaminoglycan abundant in the extracellular matrix, is important in cell migration during embryonic development, cellular proliferation, and differentiation and has a structural role in connective tissues. The turnover of HA requires endoglycosidic breakdown by lysosomal hyaluronidase, and a congenital deficiency of hya...

We have sequenced the Streptomyces plicatus β-N-acetylhexosaminidase (SpHex) gene and identified the encoded protein as a member of family 20 glycosyl hydrolases. This family includes human β-N-acetylhexosaminidases whose deficiency results in various forms of GM2 gangliosidosis. Based upon the x-ray structure of Serratia marcescens chitobiase (SmC...