Gerard Pals

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• PhD
• emeritus at Amsterdam University Medical Center

Plastin-3 (PLS3) encodes T-plastin, an actin-bundling protein mediating the formation of actin filaments by which numerous cellular processes are regulated. Loss-of-function genetic defects in PLS3 are reported to cause X-linked osteoporosis and childhood-onset fractures. However, the molecular etiology of PLS3 remains elusive. Functional compensat...

Since our discovery in 2013 that genetic defects in PLS3 lead to bone fragility, the mechanistic details of this process have remained obscure. It has been established that PLS3 variants cause syndromic and nonsyndromic osteoporosis as well as osteoarthritis. PLS3 codes for an actin-bundling protein with a broad pattern of expression. As such, it i...

Pathogenic variants in the LRP5, PLS3, or WNT1 genes can significantly affect bone mineral density, causing monogenic osteoporosis. Much remains to be discovered about the phenotype and medical care needs of these patients. The purpose of this study was to examine the use of medical care among Dutch individuals identified between 2014 and 2021 with...

Introduction Osteogenesis Imperfecta is a rare genetic connective tissue disorder, characterized by skeletal dysplasia and fragile bones. Currently only two mouse models have been reported for haploinsufficient (HI) mild Osteogenesis Imperfecta (OI); the Col1a1 +/Mov13 (Mov13) and the Col1a1 +/-365 mouse model. The Mov13 mice were created by random...

Osteocytes sense mechanical loads and transduce mechanical signals into a chemical response. They are the most abundant bone cells deeply embedded in mineralized bone matrix, which affects their regulatory activity in the mechanical adaptation of bone. The specific location in the calcified bone matrix hinders studies on osteocytes in the in vivo s...

Osteogenesis imperfecta (OI) is a heritable connective tissue disorder that causes bone fragility due to pathogenic variants in genes responsible for the synthesis of type I collagen. Efforts to classify the high clinical variability in OI led to the Sillence classification. However, this classification only partially takes into account extraskelet...

Objectives The primary aim was to gain insight into the growth of the aortic root in children and young adults with Marfan syndrome (MFS). Furthermore, we aimed to identify a clinical profile of patients with MFS who require an aortic root replacement at a young age with specific interest in age, sex, height and fibrillin-1 ( FBN1 ) genotype. Meth...

To optimize care for children with Marfan syndrome (MFS) in the Netherlands, Dutch MFS growth charts were constructed. Additionally, we aimed to investigate the effect of FBN1 variant type (haploinsufficiency [HI]/dominant negative [DN]) on growth, and compare MFS‐related height increase across populations. Height and weight data of individuals wit...

Epidermolysis bullosa (EB) is a group of rare genetic diseases that exhibit mechanical fragility of the skin. This condition will result in the occurrence of skin blisters, skin erosions, and skin ulcerations when the skin is subjected to trauma. In this case report, we present a case of EB and multiple skeletal deformities in a 21-year-old female....

Inherited bone disorders account for about 10% of documented Mendelian disorders and are associated with high financial burden. Their study requires osteoblasts which play a critical role in regulating the development and maintenance of bone tissue. However, bone tissue is not always available from patients. We developed a highly efficient platelet...

Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disease in which soft connective tissue is converted into heterotopic bone through an endochondral ossification process. Patients succumb early as they gradually become trapped in a second skeleton of heterotopic bone. Although the underlying genetic defect is long known,...

Osteogenesis Imperfecta (OI) is a complex disease caused by genetic alterations in production of collagen type I, and collagen-related proteins. Bone fragility is the most common patient issue, but extraskeletal complications also present an adverse factor in the quality of life and prognosis of patients with OI. However, still little is known abou...

Primary ciliary dyskinesia (PCD) is a heterogeneous disease, with impaired mucociliary clearance causing respiratory tract infections. A founding CCDC114 mutation has led to a relatively homogeneous and large Dutch PCD population in Volendam. Our aim was to describe their phenotype. Therefore, all Volendam PCD patients seen at the Amsterdam UMC wer...

Osteogenesis imperfecta (OI) is a syndromic disorder of bone fragility with high variation in its clinical presentation. Equally variable is molecular aetiology; recessive forms are caused by approximately 20 different genes, many of which are directly implicated in collagen type I biosynthesis. Biallelic variants in prolyl 3-hydroxylase 1 (P3H1) a...

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare progressive genetic disease effecting one in a million individuals. During their life, patients with FOP progressively develop bone in the soft tissues resulting in increasing immobility and early death. A mutation in the ACVR1 gene was identified as the causative mutation of FOP in 2006....

Osteogenesis Imperfecta (OI) comprises a heterogeneous group of patients who share bone fragility and deformities as the main characteristics, albeit with different degrees of severity. Phenotypic variation also exists in other connective tissue aspects of the disease, complicating disease classification and disease course prediction. Although coll...

Osteogenesis imperfecta (OI) is characterized primarily by susceptibility to fractures with or without bone deformation. OI is genetically heterogeneous: over 20 genetic causes are recognized. We identified bi-allelic pathogenic KDELR2 variants as a cause of OI in four families. KDELR2 encodes KDEL endoplasmic reticulum protein retention receptor 2...

In the field of rare bone diseases in particular, a broad care team of specialists embedded in multidisciplinary clinical and research environment is essential to generate new therapeutic solutions and approaches to care. Collaboration among clinical and research departments within a University Medical Center is often difficult to establish, and ma...

Mechanical stress determines bone mass and structure. It is not known whether mechanical loading affects expression of bone regulatory genes in a combined deficiency of estrogen and vitamin D. We studied the effect of mechanical loading on the mRNA expression of bone regulatory genes during vitamin D and/or estrogen deficiency. We performed a singl...

Using [18F]NaF positron emission tomography (PET) it is not only possible to identify the ossifying potency of a flare‐up, but also to identify an asymptomatic chronic stage of fibrodysplasia ossificans progressiva (FOP). The purpose of this study was to investigate the diagnostic role of a more widely available imaging modality, magnetic resonance...

The aims of this work are to isolate bacterial symbionts from nudibranchs and subsequently to determine anti-Methicillin resistant Staphylococcus aureus (MRSA), cytotoxicity and anti-Herpes simplex virus type 1 (HSV-1) activities of bio compounds. A total of 15 species of nudibranchs were collected from Karimunjawa and five species from Bali, respe...

Aim of the study: Osteogenesis imperfecta and Ehlers Danlos syndrome are hereditary disorders caused primarily by defective collagen regulation. Osteogenesis imperfecta patients were divided to haploinsufficient and dominant negative depending on the effect of COL1A1 and COL1A2 mutations whereas Ehlers Danlos syndrome patients had a mutation in PL...

Background: Thoracic aortic aneurysms and dissections (TAAD) may have a heritable cause in up to 20% of cases. We aimed to investigate the pathogenic effect of a TGFBR1 mutation in relation to TAAD. Methods: Co-segregation analysis was performed followed by functional investigations, including myogenic transdifferentiation. Results: The c.1043...

Background: Osteogenesis imperfecta (OI) is a clinically heterogeneous disease characterized by extreme skeletal fragility. It is caused by mutations in genes frequently affecting collagen biosynthesis. Mutations in CREB3L1 encoding the ER stress transducer OASIS are very rare and are only reported in pediatric patients. We report a large family w...

The aim of this work was to isolate bacterial symbionts from nudibranchs and subsequently to determine anti-Methicillin resistant Staphylococcus aureus (MRSA), cytotoxicity and anti-HSV-1 activities of bio-compounds. Fifteen species of nudibranchs were collected from Karimunjawa and five species from Bali, respectively. A total of 245 bacteria isol...

The aim of this work was to isolate bacterial symbionts from nudibranchs and subsequently to determine anti-Methicillin resistant Staphylococcus aureus (MRSA), cytotoxicity and anti-HSV-1 activities of bio-compounds. Fifteen species of nudibranchs were collected from Karimunjawa and five species from Bali, respectively. A total of 245 bacteria isol...

Marfan syndrome is named after the French pediatrician Antoine Bernard-Jean Marfan who described in 1896 a girl with arachnodactyly and long limbs1. The patient also had congenital contractures of the elbows and would not fulfill the current criteria for Marfan syndrome. She probably was suffering from a condition that we now call contractural arac...

The pathophysiology of aortic aneurysms (AA) is far from being understood. One reason for this lack of understanding is basic research being constrained to fixated cells or isolated cell cultures, by which cell-to-cell and cell-to-matrix communications are missed. We present a new, in vitro method for extended preservation of aortic wall sections t...

We aimed to determine the diagnostic yield of a targeted-exome panel in a cohort of 74 Dutch primary ciliary dyskinesia (PCD) patients. The panel consisted of 26 PCD-related and 284 candidate genes. To prioritize PCD candidate genes, we investigated the transcriptome of human airway cells of twelve healthy volunteers during in vitro ciliogenesis an...

Background: Marfan syndrome (MFS), a congenital connective tissue disorder leading to aortic aneurysm development, is caused by fibrillin-1 (FBN1) gene mutations. Transforming growth factor beta (TGF-β) might play a role in the pathogenesis. It is still a matter of discussion if and how TGF-β up-regulates the intracellular downstream pathway, alth...

Background : MFS is characterized by variable clinical manifestations mainly in cardiovascular, ocular, and skeletal systems. The major encoding gene of structural constituent of extracellular microfibrils is Fibrillin-1 (FBN1). Approximately 90% of MFS cases are caused by mutations in the FBN1 gene (15q21.1) and the other second is TGFBR2 (3p22) g...

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease with a progressive course characterized by episodically local flare-ups, which often but not always leads to heterotopic bone formation (HO). Recently, we showed that [18F]NaF PET/CT may be the first tool to monitor progression of a posttraumatic flare-up leading to new HO, which...

Fibrodysplasia Ossificans Progressiva (FOP) is a progressive disease characterized by periods of heterotopic ossification of soft connective tissues, including ligaments. Though progress has been made in recent years in unraveling the underlying mechanism, patient-derived cell models are necessary to test potential treatment options. Periodontal li...

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder leading to progressive heterotopic ossifications (HO) of muscles, tendons and ligaments which can be induced by trauma or by surgery. Despite strong medical advice to the contrary, an FOP patient insisted on surgery to alleviate her complete trismus, which caused an unbearable i...

Background: The effect of FBN1 mutation type on the severity of cardiovascular manifestations in patients with Marfan syndrome (MFS) has been reported with disparity results. Objectives: This study aims to determine the impact of the FBN1 mutation type on aortic diameters, aortic dilation rates and on cardiovascular events (ie, aortic dissection...

Mutations in genes encoding proteins of the smooth muscle cell (SMC) contractile apparatus contribute to familial aortic aneurysms. To investigate the pathogenicity of these mutations, SMC are required. We demonstrate a novel method to generate SMC-like cells from human dermal fibroblasts by transdifferentiation to study the effect of variants in g...

Defects in motile cilia and sperm flagella cause primary ciliary dyskinesia (PCD), characterized by chronic airway disease, infertility, and left-right body axis disturbance. Here we report maternally inherited and de novo mutations in PIH1D3 in four men affected with PCD. PIH1D3 is located on the X chromosome and is involved in the preassembly of...

With the advance of genomic technologies, we are now able to detect genetic variations in patients with high accuracy, whole genome scale and relatively cost-effective. This offers an opportunity for altering medical practice fundamentally as well as insurance policy. Although clinicians, scientists, and health policy makers still have to deal how...

Background Mild biventricular dysfunction is often present in patients with Marfan syndrome. Losartan has been shown to reduce aortic dilatation in patients with Marfan syndrome. This study assesses the effect of losartan on ventricular volume and function in genetically classified subgroups of asymptomatic Marfan patients without significant valvu...

Fibrodysplasia ossificans progressiva is a rare genetic disorder characterized by progressive heterotopic ossification. FOP patients develop soft tissue lumps as a result of inflammation-induced flare-ups which leads to the irreversible replacement of skeletal muscle tissue with bone tissue. Classical FOP patients possess a mutation (c.617G > A; R2...

Aims: The aorta in Marfan syndrome (MFS) patients is variably affected. We investigated the assumed genotype-effect on protein production as a risk factor for a severe aortic phenotype in adult MFS patients. Methods and results: We collected clinical and genetic data from all 570 adults with MFS who had been included in the Dutch CONgenital CORv...

Introduction Fibrodysplasia ossificans progressiva (FOP) is a rare extremely disabling congenital disorder characterized by progressive heterotopic ossifications (HO) preceded by episodic inflammatory flare ups leading to early death. Most cases are caused by the R206H mutation in the Bone Morphogenetic Protein receptor ACVR1. There is no proven ef...

Background: Transforming growth factor (TGF)-β is involved in various physiological roles from cell growth, cell differentiation, apoptosis, and some disease development. The TGF-β is tightly regulated and involves a myriad of molecules. Moreover, signal cross talk is prominent in the pathway, making it very complex and very difficult to study. Ser...

We report three families with arterial aneurysms and dissections in which variants predicted to be pathogenic were identified in SMAD2. Moreover, one variant occurred de novo in a proband with unaffected parents. SMAD2 is a strong candidate gene for arterial aneurysms and dissections given its role in the TGF-β signaling pathway. Furthermore, altho...

Loeys-Dietz syndrome is a connective tissue disorder accompanied by life-threatening vascular abnormalities such as aneurysms and dissections. Recognising the acute clinical picture is essential for rapid diagnosis and treatment. We describe three members of a family with a typical acute presentation of Loeys-Dietz syndrome, but without the charact...

Introduction: Patients with Marfan syndrome - caused by FBN1 mutations - have an increased risk of life-threatening aortic complications. It has been shown that losartan reduces aortic dilation rate in these patients. The response to losartan treatment, however, was highly variable between individuals. Here we investigate whether there is a differe...

Fibrodysplasia ossificans progressiva (FOP) is a rare congenital disorder characterized by progressive heterotopic ossification. During the disease course FOP patients present soft tissue lumps as a result of inflammation-induced flare-ups preceding the irreversible replacement of skeletal muscle tissue with bone tissue. Classical FOP patients poss...

Background: Fibrodysplasia Ossificans Progressive (FOP) is rare disease characterised by progressive heterotopic ossifications during life leading to extremely disabling immobility, thoracic insufficiency and early death. The underlying cause is a mutation in the activin A type I receptor gene. In FOP skeletal muscles and connective tissues are bei...

Different forms of Ehlers-Danlos syndrome (EDS) exist, with specific phenotypes and associated genes. Vascular EDS, caused by heterozygous mutations in the COL3A1 gene, is characterized by fragile vasculature with a high risk of catastrophic vascular events at a young age. Classic EDS, caused by heterozygous mutations in the COL5A1 or COL5A2 genes,...

Aortic dissections involving the descending aorta are a major clinical problem in patients with Marfan syndrome. The purpose of this study was to identify clinical parameters associated with type B aortic dissection and to develop a risk model to predict type B aortic dissection in patients with Marfan syndrome. Patients with the diagnosis of Marfa...

-It has been shown that losartan reduces aortic dilatation in patients with Marfan syndrome. However, treatment response is highly variable. This study investigates losartan effectiveness in genetically classified subgroups. -In this predefined sub-study of COMPARE, Marfan patients were randomized to daily receive losartan 100mg or no losartan. Aor...

Fibrodysplasia ossificans progressiva (FOP) is a rare, genetic disorder characterized by progressive heterotopic ossification preceded by flare ups. There is no treatment yet. We have developed an in vitro system to investigate trans-differentiation towards the osteogenic cell lineage using platelet lysate (PL). We hypothesize osteogenic potential...

Background Recently, we demonstrated that losartan reduced the aortic root dilatation rate (AoDR) in adults with Marfan syndrome (MFS); however, responsiveness was diverse. The aim was to determine the role of transforming growth factor-β (TGF-β) as therapeutic biomarker for effectiveness of losartan on AoDR. Methods Baseline plasma TGF-β levels o...

Creatine transporter (SLC6A8) deficiency is the most common cause of cerebral creatine syndromes, and is characterized by depletion of creatine in the brain. Manifestations of this X-linked disorder include intellectual disability, speech/language impairment, behavior abnormalities, and seizures. At the moment no effective treatment is available. I...

2. The history of diagnosing Marfan syndrome 3. The FBN1 gene 4. Overview of literature 5. Different types of FBN1 mutations 6. Conclusion 7. Expert opinion Introduction: Marfan syndrome (MFS) is a connective tissue disorder with highly variable features in cardiovascular, ocular and skeletal systems. MFS is generally caused by one of the 2900-plus...

Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder affecting motile cilia. This can lead to neonatal respiratory distress, early onset upper and lower airway infections, laterality abnormalities and sub- or infertility. Although disease progression shows large individual variability, all adult patients eventually develop extens...

Osteoporosis with its consequences, i.e., fractures, is major health problem in ageing societies. As osteoporosis is a prevalent disorder, understanding its etiological factors is very important. We recently identified novel pathogenic variants in PLS3 (encoding Plastin 3 (PLS3), a filamentous-actin bundling protein) as a cause of X-linked osteopor...

Fibrodysplasia ossificans progressiva (FOP) is a rare, extremely disabling genetic disorder characterized by progressive heterotopic ossification preceded by episodic inflammatory soft tissue swellings (flare ups) leading to early death. There is no proven effective treatment yet. We aimed to develop an in vitro system to investigate the working me...

Osteoporosis is characterized by low bone mass and micro-architectural deterioration of bone tissue, which results in bone fragility and fractures. It is a multifactorial disease which is often encountered in menopausal women. We recently identified novel pathogenic variants of the plastin 3 (PLS3) gene (Xq23) as causative factors for X-linked oste...

Osteoporosis affects a large proportion of the human population, particularly women after menopause. Recently we reported that pathogenic loss-of-function variants in the plastin 3 (PLS3) gene, localized on Xq23 are causative of familial osteoporosis and osteoporotic fractures at a young age in males and can lead to osteoporosis at a variable age i...

Osteoporosis is characterized by low bone mass and micro-architectural deterioration of bone tissue, which results in bone fragility and fractures. It is a multifactorial disease which is often encountered in menopausal women. We recently identified novel pathogenic variants of the plastin 3 (PLS3) gene (Xq23) as causative factors for X-linked oste...

Osteoporosis affects a large proportion of the human population, particularly women after menopause. Recently we reported that pathogenic loss-of-function variants in the plastin 3 (PLS3) gene, localized on Xq23 are causative of osteoporosis and osteoporotic fractures at a young age in males and can lead to osteoporosis at a variable age in females...

Background Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous ciliopathy disorder affecting cilia and sperm motility. A range of ultrastructural defects of the axoneme underlie the disease, which is characterised by chronic respiratory symptoms and obstructive lung disease, infertility and body axis laterality defects. We applied...

Objectives: Osteoporosis with fractures as an X-linked trait, was first reported as a rare type of OI by Sillence in 1980. OI is genetically heterogeneous with an estimated 90% due to dominant mutations in the COL1A1 or COL1A2 gene and approximately 10% due to recessive mutations and other unknown causes. Our goal is to discover new genetic causes...

Plastin 3 (PLS3), a protein involved in the formation of filamentous actin (F-actin) bundles, appears to be important in human bone health, on the basis of pathogenic variants in PLS3 in five families with X-linked osteoporosis and osteoporotic fractures that we report here. The bone-regulatory properties of PLS3 were supported by in vivo analyses...

Primary ciliary dyskinesia (PCD) is a ciliopathy characterized by airway disease, infertility, and laterality defects, often caused by dual loss of the inner dynein arms (IDAs) and outer dynein arms (ODAs), which power cilia and flagella beating. Using whole-exome and candidate-gene Sanger resequencing in PCD-affected families afflicted with combin...

Background: Early diagnosis and monitoring of disease activity are essential in cystic fibrosis (CF) and primary ciliary dyskinesia (PCD). We aimed to establish exhaled molecular profiles as the first step in assessing the potential of breath analysis. Methods: Exhaled breath was analyzed by electronic nose in 25 children with CF, 25 with PCD an...

Defects in motile cilia and sperm flagella cause primary ciliary dyskinesia (PCD), characterized by chronic airway disease, infertility, and left-right laterality disturbances, usually as a result of loss of the outer dynein arms (ODAs) that power cilia/flagella beating. Here, we identify loss-of-function mutations in CCDC114 causing PCD with later...

Osteogenesis imperfecta (OI) is a connective tissue disorder mostly characterized by autosomal dominant inheritance. Over 1,100 causal mutations have been identified scattered along all exons of genes encoding type I collagen precursors, COL1A1 and COL1A2. Because of the absence of mutational hotspots, Sanger sequencing is considered the gold stand...

The European Journal of Human Genetics is the official Journal of the European Society of Human Genetics, publishing high-quality, original research papers, short reports, News and Commentary articles and reviews in the rapidly expanding field of human genetics and genomics.

Thoracic aortic aneurysms and dissections (TAAD) is a serious condition with high morbidity and mortality. It is estimated that 20% of non-syndromic TAAD cases are inherited in an autosomal-dominant pattern with variable expression and reduced penetrance. Mutations in myosin heavy chain 11 (MYH11), one of several identified TAAD genes, were shown t...