A5005592998- Growth Hormone and Insulin-like Growth Factors
- Genetic Syndromes and Imprinting
- Muscle Physiology and Disorders
- Genomic variations and chromosomal abnormalities
- Connective tissue disorders research
- Lipid metabolism and disorders
- Neurogenetic and Muscular Disorders Research
- Metabolism, Diabetes, and Cancer
- Cardiomyopathy and Myosin Studies
- Genetic factors in colorectal cancer
- Genetics and Neurodevelopmental Disorders
- RNA modifications and cancer
- Genetic Neurodegenerative Diseases
- Immunodeficiency and Autoimmune Disorders
- Genomics and Rare Diseases
- DNA Repair Mechanisms
- Congenital heart defects research
- Prosthetics and Rehabilitation Robotics
- Digestive system and related health
- Heart Failure Treatment and Management
- Telomeres, Telomerase, and Senescence
- Prenatal Screening and Diagnostics
- Diabetes and associated disorders
- Metabolism and Genetic Disorders
- Protein Kinase Regulation and GTPase Signaling
Leiden University
2005-2025
Leiden University Medical Center
2013-2024
Duchenne Parent Project
2023-2024
Center for Human Genetics
2012-2013
Pediatrics and Genetics
2012
Utrecht University
2006
IGF-I is a key factor in intrauterine development and postnatal growth metabolism. The secretion of utero not dependent on GH, whereas childhood adult life, seems to be mainly controlled by as revealed from studies patients with GHRH receptor GH mutations. In 55-yr-old male, the first child consanguineous parents, presenting severe retardation, microcephaly, sensorineural deafness, we found homozygous G A nucleotide substitution gene changing valine 44 into methione. inactivating nature...
Antisense oligonucleotide (ASO) therapies present a promising disease-modifying treatment approach for rare neurological diseases (RNDs). However, the current focus is on "more common" RNDs, leaving large share of RND patients still without prospect treatments. In response to this gap, n-of-1 ASO approaches are targeting ultrarare or even private variants. While highly attractive, emerging, academia-driven field ultimately individualized precision medicine in need systematic guidance and...
The type 1 IGF-I receptor (IGF1R) mediates the biological functions of IGF-I. Binding to IGF1R results in autophosphorylation intracellular beta-subunit and activation signaling.The objective this study was evaluate functional characteristics a novel mutation describe phenotypic features two patients with mutation.The performed university hospital.We 35-yr-old female mild intrauterine growth failure, progressive postnatal retardation, severe failure thrive, microcephaly. Her daughter born...
Small for gestational age (SGA)-born children comprise a heterogeneous group in which only few genetic causes have been identified.To determine copy number variations 18 growth-related genes 100 SGA with persistent short stature.Copy (SHOX, GH1, GHR, IGF1, IGF1R, IGF2, IGFBP1-6, NSD1, GRB10, STAT5B, ALS, SOCS2, and SOCS3) were determined by an "in house" multiplex ligation-dependent probe amplification kit. The deletions further characterized single-nucleotide polymorphism array analysis.Two...
<h3>Background:</h3> Patients with a microscopically visible deletion of the distal part long arm chromosome 1 have recognisable phenotype, including mental retardation, microcephaly, growth distinct facial appearance and various midline defects corpus callosum abnormalities, cardiac, gastro-oesophageal urogenital defects, as well central nervous system anomalies. submicroscopic, subtelomeric 1qter similar suggesting that main phenotype these patients is caused by haploinsufficiency genes in...
C-type natriuretic peptide (CNP)/natriuretic receptor 2 (NPR2) signaling is essential for long bone growth. Enhanced CNP production caused by chromosomal translocations results in tall stature, a Marfanoid phenotype, and skeletal abnormalities. A similar phenotype was described family with an activating NPR2 mutation within the guanylyl cyclase domain.Here we describe extremely male without deformities, novel (p.Arg655Cys) located kinase homology domain.The objective of study to investigate...
Severe short stature can be caused by defects in numerous biological processes including IGF-1 signaling, centromere function, cell cycle control, and DNA damage repair. Many syndromic causes of are associated with medical comorbidities hypogonadism microcephaly.To identify an underlying genetic etiology two siblings severe gonadal failure.Clinical phenotyping, analysis, complemented vitro functional studies the candidate gene.An academic pediatric endocrinology clinic.Two adult (male...
GH insensitivity can be caused by defects in the receptor (GHR) or postreceptor signaling pathway. Recently, two female patients with severe growth retardation and pulmonary immunological problems were described a defect STAT5b, critical intermediary of downstream GHR signaling.The objective was to determine functional characteristics novel STAT5b mutation describe phenotype.We an adult male patient short stature [-5.9 sd score (SDS)], delayed puberty, no history problems. GH-binding protein...
Abstract Context: Microscopically visible heterozygous terminal 15q deletions encompassing the IGF1R gene are rare and usually associated with intrauterine growth retardation short stature. The incidence of submicroscopic is unknown, as effect GH therapy in this condition. Objective: objective study was to describe use a novel genetic technique [multiplex ligation probe amplification (MLPA)] detect haploinsufficiency patient suspected an defect evaluate long-term therapy. Patient: A...
The phenotype and response to GH treatment of children with an IGF1R defect is insufficiently known. To develop a clinical score for selecting short stature genetic testing evaluate the efficacy treatment. Case series identified in university laboratory. Of all patients sufficient data, 18 had (likely) pathogenic mutations (group 1) 7 15q deletions including 2); 19 were treated GH. Phenotype In groups 1 2, mean (range) birth weight, length, head circumference (HC) SD scores (SDSs) −2.1 (−3.7...
To date, 16 IGFALS mutations in 21 patients with acid-labile subunit (ALS) deficiency have been reported. The impact of heterozygosity for on growth is unknown.The study evaluates the heterozygous expression phenotype based data collected by International ALS Consortium.Patient information was derived from Registry, which includes and family members who were either carriers or homozygous wild-type. Within each family, effect stature analyzed as follows: 1) two mutant alleles (2ALS) vs....
Acid-labile subunit (ALS) deficiency due to homozygous inactivation of the ALS gene (IGFALS) is associated with moderate short stature, and in few cases pubertal delay. The clinical expression heterozygosity unknown.To investigate clinical, laboratory, radiological features heterozygous carriers a novel mutation comparison non-carriers.Three Kurdish brothers their relatives.The index presented microcephaly, low circulating IGF-I IGF-binding protein-3 (IGFBP-3), undetectable levels. Two were...
Homozygous IGF1 deletions or mutations lead to severe short stature, deafness, microcephaly, and mental retardation. Heterozygosity for an IGF-I defect may modestly decrease height head circumference.The objective of the study was investigate clinical features heterozygous carriers a novel mutation in gene comparison with noncarriers family establish effect human GH treatment.Two children, their mother, maternal grandfather carried were compared two relatives who noncarriers.The index cases...
In short children, a low IGF-I and normal GH secretion may be associated with various monogenic causes, but their prevalence is unknown. We aimed at testing GH1, GHR, STAT5B, IGF1, IGFALS in children insensitivity.Patients were divided into three groups: group 1 (height SDS <-2.5, <-2 SDS, n = 9), 2 -2.5 to -1.9, 6) 3 <-1.9, -2 0 21). An generation test was performed 11 patients. Genomic DNA used for direct sequencing, multiplex ligation-dependent probe amplification whole-genome SNP array...
Objective Mutations of the fibroblast growth factor receptor 3 ( FGFR3 ) cause various forms short stature, which least severe phenotype is hypochondroplasia, mainly characterized by disproportionate stature. Testing for an mutation currently not part routine diagnostic testing in children with stature without disproportion. Design A three-generation family dominantly transmitted proportionate was studied whole-exome sequencing to identify causal gene mutation. Functional studies and protein...
Silver-Russell syndrome (SRS) is a heterogeneous disorder characterized by intrauterine and postnatal growth retardation. HMGA2 variants are rare cause of SRS its functional role in human linear unclear. Patients with suspected negative for 11p15LOM/mUPD7 underwent whole-exome and/or targeted-genome sequencing. Mutant protein expression nuclear localization were assessed. Two Hmga2-knockin mouse models generated. Five clinical patients harbored differing impacts: 2 stop-gain nonsense...
Abstract Context The growth hormone (GH) secretagogue receptor, encoded by GHSR, is expressed on somatotrophs of the pituitary gland. Stimulation with its ligand ghrelin, as well constitutive activity, enhances GH secretion. Studies in knock-out mice suggest that heterozygous loss-of-function GHSR associated decreased response to fasting, but patient observations small case reports have been equivocal. Objective To establish phenotype haploinsufficiency and their treatment. Methods This...
In recent years, numerous heterozygous ACAN variants have been identified in individuals with short stature. The phenotypic spectrum includes mild to moderate stature, advanced delayed bone age, dysmorphic features, brachydactyly and/or other skeletal defects and joint pathology early adulthood which often requires surgery. However, only one multiexonic deletion has reported date, a family age childhood osteoarthritis spine deformity the father. Here, we describe 15 from 6 families...
<b><i>Background/Aims:</i></b> In addition to genome-wide association studies (GWAS), height-associated genes may be uncovered by studying individuals with extreme short or tall stature. <b><i>Methods:</i></b> Genome-wide analysis for copy number variants (CNVs), using single nucleotide polymorphism (SNP) arrays, was performed in 49 index cases born small gestational age persistent Segregation performed, and CNVs were compared information from...
Objective : STAT5b is a component of the GH signaling pathway. Recently, we described 31-year-old male patient (height, −5.9 SDS) with novel homozygous inactivating mutation in gene. The purpose this study to describe phenotype detail, including secretion and immunological function. In addition, report four family members patient, all heterozygous carriers mutation. Design methods Twenty-four hour prolactin characteristics were assessed by blood sampling at 10-min intervals. An IGF-I...
Abstract Becker muscular dystrophy (BMD) is the milder allelic variant of Duchenne dystrophy, with higher dystrophin levels. To anticipate on results interventions targeting expression it important to know natural variation between different muscles and over time. Dystrophin was quantified using capillary Western immunoassay (Wes) in anterior tibial (TA) muscle 37 BMD patients. Variability studied two samples from same TA biopsy site nine patients, assessing longitudinal biopsies, eight...
Abstract IGFs are critical for normal intrauterine and childhood growth sustaining health throughout life. We showed previously that the production of IGF-1 IGF-2 requires interaction with chaperone glucose-regulated protein 94 (GRP94) amount secreted is proportional to GRP94 activity. Therefore, we tested hypothesis functional polymorphisms human affect IGF thereby health. describe a hypomorphic variant GRP94, P300L, whose heterozygous carriers have 9% lower circulating concentration. P300L...