Martine Tetreault

• PhD
• Assistant Professor at Centre hospitalier de l'Université de Montréal (CHUM)

While international efforts have characterized genetic variation in millions of individuals, the interplay of environmental, social, cultural, and genetic factors is poorly understood for most worldwide populations. The province of Quebec in Canada has been the site of numerous genetic studies, often focusing on individual Mendelian diseases in fou...

Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) is a highly abundant RNA binding protein alternatively spliced in two main isoforms named, hnRNP A1 and hnRNP A1B. While being ubiquitously expressed, both isoforms have different cellular localizations and are differentially expressed in tissues during development and aging. To improve our under...

Coronavirus disease 2019 (COVID-19) is a multi-systemic illness that became a pandemic in March 2020. Although environmental factors and comorbidities can influence disease progression, there is a lack of prognostic markers to predict the severity of COVID-19 illness. Identifying these markers is crucial for improving patient outcomes and appropria...

Background Pheochromocytomas (PCCs) and paragangliomas (PGLs) (PPGLs) are rare tumours arising from the chromaffin cells. There is evidence suggesting a link between hypoxemia and PPGLs. Chronic hypoxia can lead to gain of function somatic variants in the EPAS1 gene that encodes for hypoxia-inducible factor 2-alpha (HIF-2α), involved in PPGL tumori...

Disclosure: S. Parisien-La Salle: None. G. Van Vliet: None. G. Corbeil: None. M. Labrecque: None. M. Tétreault: None. I. Bourdeau: None. Introduction: Primary aldosteronism is a frequent cause of secondary hypertension in adults but is rare in children. We report the case and genetic studies of an 11 yo girl presenting with primary aldosteronism at...

Lipids are essential for neuron development and physiology. Yet, the central hubs that coordinate lipid supply and demand in neurons remain unclear. Here, we combine invertebrate and vertebrate models to establish the presence and functional significance of neuronal lipid droplets (LD) in vivo . We find that LD are normally present in neurons in a...

We studied three brothers and a maternal half‐brother featuring global developmental delay, mild to moderate intellectual disability, epilepsy, microcephaly, and strabismus. All had bilateral perisylvian and perirolandic polymicrogyria, while some also had malformations of the hippocampus (malrotation and dysplasia), cerebellum (heterotopias and as...

Lifestyle factors modulate dementia risk. We investigated mechanisms of dementia risk reduction by emerging dietary ketogenic interventions. We show that distinct interventions, a medium-chain triglycerides (MCT)-enriched diet and a carbohydrate-free, high-fat diet (CFHF), improve cognition and dendritic spine density of memory-associated hippocamp...

Parkinson’s Disease (PD) is most recognized for its impact on the central nervous system. However, recent breakthroughs underscore the crucial role of interactions between central and peripheral systems in PD’s pathogenesis. The spotlight is now shifting as we explore beyond the central nervous system, discovering that peripheral changes such as in...

DNA replication and repair are basic yet essential molecular processes for all cells. RFC1 encodes the largest subunit of the Replication Factor C (RFC), which is a clamp-loader during DNA replication and repair. Intronic repeat expansion in RFC1 has recently been associated with so-called RFC1-related disorders, which mainly encompass late-onset c...

Plasma RNAemia, delayed antibody responses and inflammation predict COVID-19 outcomes, but the mechanisms underlying these immunovirological patterns are poorly understood. We profile 782 longitudinal plasma samples from 318 hospitalized patients with COVID-19. Integrated analysis using k-means reveals four patient clusters in a discovery cohort: m...

Preserving the in vivo cell transcriptome is essential for accurate profiling, yet factors during cell isolation including time ex vivo and temperature induce artifactual gene expression, particularly in stress-responsive immune cells. In this study, we investigated two methods to mitigate ex vivo activation signature gene (ASG) expression in perip...

Preserving the in vivo cell transcriptome is essential for accurate profiling, yet factors during cell isolation including time ex vivo and temperature induce artifactual gene expression, particularly in stress-responsive immune cells. In this study, we investigated two methods to mitigate ex vivo activation signature gene (ASG) expression in perip...

Plasma RNAemia, delayed antibody responses and inflammation predict COVID-19 outcomes, but the mechanisms underlying these immunovirological patterns are poorly understood. We profile 782 longitudinal plasma samples from 318 hospitalized COVID-19 patients. Integrated analysis using k-means reveal four patient clusters in a discovery cohort: mechani...

Background: The late-onset cerebellar ataxias (LOCAs) have until recently resisted molecular diagnosis. Contributing to this diagnostic gap is that non-coding structural variations, such as repeat expansions, are not fully accessible to standard short-read sequencing analysis. Methods: We combined bioinformatics analysis of whole-genome sequencing...

BACKGROUND The late-onset cerebellar ataxias (LOCAs) have largely resisted molecular diagnosis. METHODS We sequenced the genomes of six persons with autosomal dominant LOCA who were members of three French Canadian families and identified a candidate pathogenic repeat expansion. We then tested for association between the repeat expansion and disea...

The human microbiota is believed to influence health. Microbiome dysbiosis may be linked to neurological conditions like Alzheimer’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. We report the ability of a probiotic bacterial strain in halting neurodegeneration phenotypes. We show that Lacticaseibacillus rhamnosus HA-114 is neur...

Despite the growing accessibility of clinical sequencing, functional interpretation of variants remains a major hurdle to molecular diagnostics of Mendelian diseases. We aimed to describe a new adult-onset myopathy with muscle weakness and hyperCKemia caused by a nonsense variant in muscular LMNA-interacting protein (MLIP). Following RNA-sequencing...

Despite advances in COVID-19 management, identifying patients evolving toward death remains challenging. To identify early predictors of mortality within 60 days of symptom onset (DSO), we performed immunovirological assessments on plasma from 279 individuals. On samples collected at DSO11 in a discovery cohort, high severe acute respiratory syndro...

Niemann–Pick type C (NP-C) disease is an autosomal recessive disease caused by variants in the NPC1 or NPC2 genes. It has a large range of symptoms depending on age of onset, thus making it difficult to diagnose. In adults, symptoms appear mainly in the form of psychiatric problems. The prevalence varies from 0.35 to 2.2 per 100,000 births dependin...

TDP-43 nuclear depletion and concurrent cytoplasmic accumulation in vulnerable neurons is a hallmark feature of progressive neurodegenerative proteinopathies such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cellular stress signalling and stress granule dynamics are now recognized to play a role in ALS/FTD pathogenesis....

Niemann–Pick disease type C (NPC) is a treatable autosomal recessive neurodegenerative condition which leads to a variety of progressive manifestations. Despite most cases being diagnosed at a young age, disease prevalence may be underestimated, especially in adults, and interpretation of NPC1 and NPC2 variants can be difficult. This study aims to...

Despite advances in COVID-19 management, it is unclear how to recognize patients who evolve towards death. This would allow for better risk stratification and targeting for early interventions. However, the explosive increase in correlates of COVID-19 severity complicates biomarker prioritisation. To identify early biological predictors of mortalit...

TDP-43 nuclear depletion and concurrent cytoplasmic accumulation in vulnerable neurons is a hallmark feature of progressive neurodegenerative proteinopathies such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cellular stress signalling and stress granule dynamics are now recognized to play a role in ALS/FTD pathogenesis....

Background Cerebellar atrophy is a nonspecific imaging finding observed in a number of neurological disorders. Genetic ataxias associated with cerebellar atrophy are a heterogeneous group of conditions, rendering the approach to diagnosis challenging. Objectives To define the spectrum of genetic ataxias associated with cerebellar atrophy in a Cana...

The human microbiota is believed to influence health. Microbiome dysbiosis may be linked to neurological conditions like Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD). We report the ability of a probiotic bacterial strain in reversing neurodegeneration phenotypes. We show that Lacticaseibacillus rhamnos...

A molecular diagnosis of LGMDR1 established by RNA sequencing - Stefan Nicolau, Karine Choquet, Eric Bareke, Yi-Hong Shao, Bernard Brais, Erin K. O’Ferrall, Martine Tétreault, J. Karamchandani

Objective: To investigate the pathogenicity of a novel homozygous BRAT1 variant in 2 siblings with nonprogressive cerebellar ataxia (NPCA) through functional studies on primary and immortalized patient cell lines. Methods: BRAT1 protein levels and ataxia-telangiectasia mutated (ATM) kinase activity in patient-derived and control cell lines were...

Background: Cerebellar atrophy is characterized by loss of cerebellar tissue, with evidence on brain imaging of enlarged interfolial spaces compared to the foliae. Genetic ataxias associated with cerebellar atrophy are a heterogeneous group of disorders. We investigated the prevalence in Canada and the diagnostic yield of whole exome sequencing (WE...

Short‐chain enoyl‐CoA hydratase (SCEH or ECHS1) deficiency is a rare inborn error of metabolism caused by biallelic mutations in the gene ECHS1 (OMIM 602292). Clinical presentation includes infantile‐onset severe developmental delay, regression, seizures, elevated lactate, and brain MRI abnormalities consistent with Leigh syndrome (LS). Characteris...

Intellectual disability (ID) affects 1-2% of the general population and up to 50% of those with ID are estimated to have an underlying genetic cause. Next-generation sequencing provides an efficient means to identify the molecular causes of monogenic forms of ID. Here we present an 18 year old male with severe ID, absent speech, microcephaly, ataxi...

SHORT syndrome is a rare, recognizable syndrome resulting from heterozygous mutations in PIK3R1 encoding a regulatory subunit of phosphoinositide-3-kinase (PI3K). The condition is characterized by short stature, intrauterine growth restriction, lipoatrophy and a facial gestalt involving a triangular face, deep set eyes, low hanging columella and sm...

Deficiencies of mitochondrial respiratory chain complex I frequently result in leukoencephalopathy in young patients, and different mutations in the genes encoding its subunits are still being uncovered. We report two patients with cystic leukoencephalopathy and complex I deficiency with recessive mutations in NDUFA2, an accessory subunit of comple...

The inherited peripheral neuropathies (IPNs) are characterized by marked clinical and genetic heterogeneity and include relatively frequent presentations such as Charcot-Marie-Tooth disease and hereditary motor neuropathy, as well as more rare conditions where peripheral neuropathy is associated with additional features. There are over 250 genes kn...

Defects in mRNA export from the nucleus have been linked to various neurodegenerative disorders. We report mutations in the gene MCM3AP, encoding the germinal center associated nuclear protein (GANP), in nine affected individuals from five unrelated families. The variants were associated with severe childhood onset primarily axonal (four families)...

There are over 150 known human proteins which are tethered to the cell surface via glycosylphosphatidylinositol (GPI) anchors. These proteins play a variety of important roles in development, and particularly in neurogenesis. Not surprisingly, mutations in the GPI anchor biosynthesis and remodeling pathway cause a number of developmental disorders....

Deleterious variants in the same gene present in 2 or more families with overlapping clinical features provides convincing evidence of a disease-gene association; this can be a challenge in the study of ultra-rare diseases. To facilitate the identification of additional families, several groups have created "matching" platforms. We describe four in...

Mitochondrial protein synthesis is initiated by formylated tRNA-methionine, which requires the activity of MTFMT, a methionyl-tRNA formyltransferase. Mutations in MTFMT have been associated with Leigh syndrome, early-onset mitochondrial leukoencephalopathy, microcephaly, ataxia, and cardiomyopathy. We identified compound heterozygous MTFMT mutation...

XRCC1 is a molecular scaffold protein that assembles multi-protein complexes involved in DNA single-strand break repair. Here we show that biallelic mutations in the human XRCC1 gene are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia. Cells from a patient with mutations in XRCC1 exhibited not only reduced...

View largeDownload slide Congenital myopathies are a heterogeneous group of neuromuscular diseases, in which the genetic basis is unknown in about half of patients. Vasli et al. report that homozygous mutations leading to premature stop codons in the ZAK gene, which encodes a MAP triple kinase, cause congenital myopathy with fibre type disproporti...

The clinical translation of next-generation sequencing has created a paradigm shift in the diagnostic assessment of individuals with suspected rare genetic diseases. Whole-exome sequencing (WES) simultaneously examines the majority of the coding portion of the genome and is rapidly becoming accepted as an efficient alternative to clinical Sanger se...

Encephalocraniocutaneous lipomatosis (ECCL) is a sporadic condition characterized by ocular, cutaneous, and central nervous system anomalies. Key clinical features include a well-demarcated hairless fatty nevus on the scalp, benign ocular tumors, and central nervous system lipomas. Seizures, spasticity, and intellectual disability can be present, a...

Mutations in GALC cause Krabbe disease. This autosomal recessive leukodystrophy generally presents in early infancy as a severe disorder, but sometimes manifests as a milder adult-onset disease with spastic paraplegia as the main symptom. We recruited a family with five affected individuals presenting with adult-onset predominant cerebellar ataxia...

Lateral meningocele syndrome (LMS), or Lehman syndrome, is a rare disorder characterized by multiple lateral spinal meningoceles, distinctive facial features, joint hypermobility and hypotonia, along with skeletal, cardiac, and urogenital anomalies. Heterozygous NOTCH3 mutations affecting the terminal exon 33 were recently reported as causative in...

Ion channel proteins are required for both the establishment of resting membrane potentials and the generation of action potentials. Hundreds of mutations in genes encoding voltage-gated ion channels responsible for action potential generation have been found to cause severe neurological diseases. In contrast, the roles of voltage-independent "leak...

Hereditary cerebellar ataxias and hereditary spastic paraplegias are clinically and genetically heterogeneous and often overlapping neurological disorders. Mutations in SPG7 cause the autosomal recessive spastic paraplegia type 7 (SPG7), but recent studies indicate that they are also one of the most common causes of recessive cerebellar ataxia. In...

Manganese (Mn) and zinc (Zn) are essential divalent cations used by cells as protein cofactors; various human studies and animal models have demonstrated the importance of Mn and Zn for development. Here we describe an autosomal-recessive disorder in six individuals from the Hutterite community and in an unrelated Egyptian sibpair; the disorder is...

Mitochondrial fission and fusion are dynamic processes vital to mitochondrial quality control and the maintenance of cellular respiration. In dividing mitochondria, membrane scission is accomplished by a dynamin-related GTPase, DNM1L, that oligomerizes at the site of fission and constricts in a GTP-dependent manner. There is only a single previous...

Skeletal dysplasias are highly variable Mendelian phenotypes. Molecular diagnosis of skeletal dysplasias is complicated by their extreme clinical and genetic heterogeneity. We describe a clinically recognizable autosomal-recessive disorder in four affected siblings from a consanguineous Saudi family, comprising progressive spondyloepimetaphyseal dy...

Protein translation is an essential cellular process initiated by the association of a methionyl-tRNA with the translation initiation factor eIF2. The Met-tRNA/eIF2 complex then associates with the small ribosomal subunit, other translation factors, and mRNA, which together comprise the translational initiation complex. This process is regulated by...

A major challenge in current exome sequencing in autosomal recessive (AR) families is the lack of an effective method to prioritize single-nucleotide variants (SNVs). AR families are generally too small for linkage analysis, and length of homozygous regions is unreliable for identification of causative variants. Various common filtering steps usual...

Leigh syndrome (LS) is a rare heterogeneous progressive neurodegenerative disorder usually presenting in infancy or early childhood. Clinical presentation is variable and includes psychomotor delay or regression, acute neurological or acidotic episodes, hypotonia, ataxia, spasticity, movement disorders, and corresponding anomalies of the basal gang...

Multiple symmetric lipomatosis (MSL) is a mitochondrial disorder with impaired brown fat metabolism that has been associated with MERFF mutations in some, but not all patients. We studied a sibling pair and an unrelated individual who presented with multiple symmetric lipomatosis (MSL) and neuropathy to determine the genetic etiology of this disord...

Secreted protein, acidic, cysteine-rich (SPARC) is a glycoprotein that binds to collagen type I and other proteins in the extracellular matrix. Using whole-exome sequencing to identify the molecular defect in two unrelated girls with severe bone fragility and a clinical diagnosis of osteogenesis imperfecta type IV, we identified two homozygous vari...

Whole-exome sequencing (WES) represents a significant breakthrough in the field of human genetics. This technology has largely contributed to the identification of new disease-causing genes and is now entering clinical laboratories. WES represents a powerful tool for diagnosis and could reduce the 'diagnostic odyssey' for many patients. In this rev...

Late-onset painful sensory neuropathies are usually acquired conditions associated with common diseases. Adult presentations of known hereditary forms are often accompanied by other organ involvement. We recruited a large French-Canadian family with a dominantly inherited late-onset painful sensory neuropathy. The main clinical feature is recurrent...

Muscle mass and strength are variable traits in humans. Many French Canadians (FC) became international celebrities because of their exceptional strength. Though muscle hypertrophy has been associated in many mammals with myostatin mutations, to date only a single pediatric case has been reported in humans. Dominant pathological mutations in the CL...

Cerebellar dysplasia with cysts (CDC) is an imaging finding typically seen in combination with cobblestone cortex and congenital muscular dystrophy in individuals with dystroglycanopathies. More recently, CDC was reported in seven children without neuromuscular involvement (Poretti-Boltshauser syndrome). Using a combination of homozygosity mapping...

Whole-exome sequencing (WES) has transformed our ability to detect mutations causing rare diseases. FORGE (Finding Of Rare disease GEnes) and Care4Rare Canada are nation-wide projects focused on identifying disease genes using WES and translating this technology to patient care. Rare forms of epilepsy are well-suited for WES and we retrospectively...

Background: Leukodystrophies are a heterogeneous group of inherited neurodegenerative disorders characterised by abnormal central nervous system white matter. Mutations in POLR3A and POLR3B genes were recently reported to cause four clinically overlapping hypomyelinating leukodystrophy phenotypes. Our aim was to investigate the presence and freque...

Background: The growing number of spastic ataxia of Charlevoix-Saguenay (SACS) gene mutations reported worldwide has broadened the clinical phenotype of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The identification of Quebec ARSACS cases without two known SACS mutation led to the development of a multi-modal genomic strate...

The objective was to define clinical criteria for a novel autosomal dominant (AD) herculean painful myopathy. We reviewed the clinical assessment of 74 cases that presented with myalgia, muscle cramps, increased muscle bulk, above normal strength with a negative electrophysiological and genetic workup. We evaluated 42 members of the largest family...

FB and HV mutants correspond to Aats-met and degenerative phenotypes in HV/FB escapers. (A) After rough mapping with seven widely spaced P-elements were used (unpublished data), four P-elements were used to refine the locus. Deficiency complementation tests in this area were performed to identify four overlapping ones that uncovered a 120 Kb region...

Respiratory chain enzyme activities of isolated sonicated mitochondria from control and Aats-met mutant larvae. The enzyme activities, with means and standard deviations, for Complexes I, II, III, IV, and Citrate Synthase are listed. The genotypes used were control (FRT82B isogenized), HV/Df, and FB/Df. (PDF)

Drosophila and human mitochondrially encoded proteins possess many methionines. The Drosophila and human mitochondrially encoded proteins are listed in the first column. The Respiratory Complex that they each belong to is listed in the second column. The number of methionines and methionine percentage of the Drosophila proteins is listed in the thi...

Mitochondrial protein synthesis. Quantification of mitochondrial protein synthesis shows a generalized deficiency in the patients homozygous for the common mutation (54%, 67%, and 79% of the average of controls). On the other hand, patients who are compound heterozygous for MARS2 mutations have normal mitochondrial translation (89%, 107%, and 118%...

Homozygosity mapping by SNP microarray analysis. Homozygosity and haplotype analysis of DNA samples from nine patients belonging to five ARSAL families. Homozygosity spans over 50 Mb in Family B (unpublished data). Three common haplotypes on chromosome 2q33–34 surrounding the MARS2 region were identified (indicated in light grey for Dup1, dark grey...

Primers used. The primers used for quantitative PCR, sequencing of the MARS2 genomic region and cDNA, and for the CNV assays are displayed. (PDF)

AARS diseases. These 12 AARS-related diseases, the responsible genes, and their documented clinical phenotypes are listed. Note that those genes with a “2” at the end of their name (i.e., MARS2, DARS2, RARS2, YARS2, HARS2, AARS2, SARS2, and LARS2) are purely mitochondrial tRNA synthetases. GARS and KARS encode both the mitochondrial and cytoplasmic...

Upregulation of the mitochondrial unfolded protein response without concomitant cytoplasmic UPR response. (A) A control adult eye (y w eyFLP; FRT82B iso/FRT82B w+ cl) stained with anti-Hsp60, a protein that has been implicated as a marker of the UPRmt. (B) A mutant eye (y w eyFLP; FRT82B Aats-metFB/FRT82B w+ cl) stained with anti-Hsp60 shows a mark...

Mitochondrial tRNAs are stable in ARSAL patient cells, and loss of MARS2 in cells results in impaired mitochondrial translation. (A) Total steady-state levels of mitochondrial (mt) tRNA-met in patients and controls are similar, suggesting that decreased amino-acylation does not interfere with the stability of mt tRNA-met. mt tRNA-glu was used as a...

Pathologic Aats-met model. The model can be summarized as follows. Mutations in Aats-met result in impaired translation of the 13 components of Complexes I, III, IV, and V that are encoded in the mitochondrial genome. This results in impaired complex formation, a mitochondrial UPR, and an uncoupled respiratory chain. The resulting ROS causes tissue...