Gudrun Rappold

Gudrun Rappold
Universität Heidelberg · Institute of Human Genetics

Professor

About

339
Publications
41,041
Reads
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16,070
Citations
Citations since 2016
76 Research Items
5761 Citations
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Introduction
The focus of our research interest is on the molecular elucidation of human disease with a special focus on growth and neuronal/neuropsychiatric disorders. To uncover the basic mechanisms on the causes of these disorders, our work employs different cell culture and animal models and differentiated mouse and human induced pluripotent stem cells. We would like to understand how mutations correlate with disease, how genes are regulated and how they contribute to differentiation and development.

Publications

Publications (339)
Article
Full-text available
Argument Moreau (2019) has raised concerns about the use of DNA data obtained from vulnerable populations, such as the Uighurs in China. We discuss another case, situated in Europe and with a research history dating back 100 years: genetic investigations of Roma. In our article, we focus on problems surrounding representativity in these studies. We...
Article
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Background: Single-nucleotide polymorphisms (SNPs) of the serotonin type 3 receptor subunit (HTR3) genes have been associated with psychosomatic symptoms, but it is not clear whether these associations exist in irritable bowel syndrome (IBS). Aim: To assess the association of HTR3 polymorphisms with depressive, anxiety, and somatization symptoms...
Article
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Significance FOXP1 haploinsufficiency underlies cognitive and motor impairments in individuals with FOXP1 syndrome. Here, we show that mice lacking one Foxp1 copy exhibit similar behavioral deficits, which may be caused by striatal dysfunction. Indeed, Foxp1 +/− striatal medium spiny neurons display reduced neurite branching, and we show altered mi...
Article
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Reduced cognitive flexibility, characterized by restricted interests and repetitive behavior, is associated with atypical memory performance in autism spectrum disorder (ASD), suggesting hippocampal dysfunction. FOXP1 syndrome is a neurodevelopmental disorder characterized by ASD, language deficits, global developmental delay, and mild to moderate...
Chapter
The past decade has seen a wealth of discoveries that have led to the elucidation and understanding of neurodevelopmental disorders, including mental retardation and autism spectrum disorder. These successes were made possible by methodological advances in array diagnostics and next-generation sequencing. As a result, the causes of more than half o...
Article
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Background There is increasing evidence that Parkinson’s disease (PD) might start in the gut, thus involving and compromising also the enteric nervous system (ENS). At the clinical onset of the disease the majority of dopaminergic neurons in the midbrain is already destroyed, so that the lack of early biomarkers for the disease represents a major c...
Article
Full-text available
Congenital primary hypothyroidism (CH; OMIM 218700) is characterized by an impaired thyroid development, or dyshormonogenesis, and can lead to intellectual disability and growth retardation if untreated. Most of the children with congenital hypothyroidism present thyroid dysgenesis, a developmental anomaly of the thyroid. Various genes have been as...
Article
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Mutations in SHANK genes play an undisputed role in neuropsychiatric disorders. Until now, research has focused on the postsynaptic function of SHANKs, and prominent postsynaptic alterations in glutamatergic signal transmission have been reported in Shank KO mouse models. Recent studies have also suggested a possible presynaptic function of SHANK p...
Article
Analysis of how papers and databases are handled and interpreted shows that geneticists in Europe must stamp out unethical research practices at home, not just abroad. Analysis of how papers and databases are handled and interpreted shows that geneticists in Europe must stamp out unethical research practices at home, not just abroad.
Preprint
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There is increasing evidence that mitochondrial homeostasis - influenced by both genetic and environmental factors - is crucial in neurodevelopment. FOXP1 syndrome is a neurodevelopmental disorder that manifests motor dysfunction, intellectual disability, autism and language impairment. In this study, we used a Foxp1 +/- mouse model to address whet...
Article
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Human growth is a complex trait. A considerable number of gene defects have been shown to cause short stature, but there are only few examples of genetic causes of non-syndromic tall stature. Besides rare variants with large effects and common risk alleles with small effect size, oligogenic effects may contribute to this phenotype. Exome sequencing...
Article
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Irritable bowel syndrome (IBS) is a gut‐brain disorder in which symptoms are shaped by serotonin acting centrally and peripherally. The serotonin transporter gene SLC6A4 has been implicated in IBS pathophysiology, but the underlying genetic mechanisms remain unclear. We sequenced the alternative P2 promoter driving intestinal SLC6A4 expression and...
Article
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SHOX deficiency causes a spectrum of clinical phenotypes related to skeletal dysplasia and short stature, including Léri-Weill dyschondrosteosis, Langer mesomelic dysplasia, Turner syndrome, and idiopathic short stature. SHOX controls chondrocyte proliferation and differentiation, bone maturation, and cellular growth arrest and apoptosis via transc...
Article
The homeodomain transcription factor SHOX2 is involved in the development and function of the heart's primary pacemaker, the sinoatrial node (SAN), and has been associated with cardiac conduction-related diseases such as atrial fibrillation and sinus node dysfunction. To shed light on Shox2-dependent genetic processes involved in these diseases, we...
Article
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SHANK2 mutations have been identified in individuals with neurodevelopmental disorders, including intellectual disability and autism spectrum disorders (ASD). Using CRISPR/Cas9 genome editing, we obtained SH-SY5Y cell lines with frameshift mutations on one or both SHANK2 alleles. We investigated the effects of the different SHANK2 mutations on cell...
Article
Still little is known about the nature of the gastrointestinal pathological alterations occurring in Parkinson’s disease (PD). Here, we used multiplexed mRNA profiling to measure the expression of a panel of 770 genes related to neuropathological processes in deep submucosal rectal biopsies of PD patients and healthy controls. Altered enteric neuro...
Article
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Two human induced pluripotent stem cell lines (hiPSC) were generated by reprogramming fibroblasts isolated from a skin biopsy taken from a female patient diagnosed with autism spectrum disorder (ASD) and intellectual disability (ID). This patient harbors a de novo 120 kb deletion in SHANK2. As controls, four lines were generated in a similar manner...
Preprint
Full-text available
Moreau (2019) has raised concerns about the usage of DNA data obtained from vulnerable populations, such as the Uighurs in China. We discuss another case, situated in Europe and with a research history dating back 100 years: genetic investigations of Roma. While Moreau is mainly concerned with ethical issues, especially regarding informed consent,...
Article
Full-text available
Hirschsprung disease (HSCR, OMIM 142623) involves congenital intestinal obstruction caused by dysfunction of neural crest cells and their progeny during enteric nervous system (ENS) development. HSCR is a multifactorial disorder; pathogenetic variants accounting for disease phenotype are identified only in a minority of cases, and the identificatio...
Preprint
Full-text available
Background: There is increasing evidence that Parkinson’s disease (PD) might start in the gut, thus involving and compromising also the enteric nervous system (ENS). At the clinical onset of the disease the majority of dopaminergic neurons in the midbrain is already destroyed, so that the lack of early biomarkers for the disease represents a major...
Article
Full-text available
Patient-specific human induced pluripotent stem cells (hiPSCs) offer unprecedented opportunities for the investigation of multigenic disease, personalized medicine, and stem cell therapy. For heterogeneous diseases such as atrial fibrillation (AF), however, precise correction of the associated mutation is crucial. Here, we generated and corrected h...
Article
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Intellectual disability (ID) is a highly heterogeneous genetic condition with more than a thousand genes described so far. By exome sequencing of two consanguineous families presenting hallmark features of ID, we identified two homozygous variants in two genes previously associated with autosomal recessive ID: NDST1 (c.1966G>A; p.Asp656Asn) and MET...
Preprint
Parkinson's disease (PD) usually has a late clinical onset. The lack of early biomarkers for the disease represents a major challenge for developing timely treatment interventions. Here, we use an alpha-synuclein-overexpressing transgenic (Th-1-SNCA-A30P) mouse model of PD to identify appropriate candidate markers in the gut for early stages of PD...
Article
Background: Congenital primary hypothyroidism (CH) is the most common endocrine disorder in neonates. Methods: To identify novel genes, we performed whole exome sequencing (WES) in 6 patients with CH due to thyroid dysgenesis (TD). The potential effects of the most relevant variants were analyzed using in silico prediction tools. The most promis...
Article
Background A Giardia outbreak in Bergen, Norway, caused postinfectious functional gastrointestinal disorders (PI‐FGIDs). Despite the devastating effects of this outbreak, it presented a unique chance to investigate the implication on the dysregulation of genetic pathways in PI‐FGID. Methods We performed the first comparative expression profiling o...
Article
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The neuropathological hallmarks of Parkinson’s disease include preferential vulnerability of dopaminergic neurons of the substantia nigra pars compacta, and accumulation of intraneuronal protein inclusions known as Lewy bodies. These inclusions contain, among other proteins, aggregated alpha-synuclein and histone deacetylase 6 (HDAC6). In our study...
Article
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The significance of SHANK proteins in human behaviour is evidenced by the wide spectrum of neuropsychiatric disorders in patients with SHANK mutations and the variety of behavioural impairments of Shank knockout mouse lines. Differentially expressed SHANK isoforms might explain this complexity. The analysis of three conventional and seven condition...
Article
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Background and objectives: Pluripotent embryonic stem (ES) cells represent a perfect model system for the investigation of early developmental processes. Besides their differentiation into derivatives of the three primary germ layers, they can also be differentiated into derivatives of the 'fourth' germ layer, the neural crest (NC). Due to its mul...
Article
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Gastrointestinal dysfunctions in individuals with autism spectrum disorder are poorly understood, although they are common among this group of patients. FOXP1 haploinsufficiency is characterized by autistic behavior, language impairment, and intellectual disability, but feeding difficulties and gastrointestinal problems have also been reported. Whe...
Article
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Sinus node dysfunction (SND) and atrial fibrillation (AF) often coexist; however, the molecular mechanisms linking both conditions remain elusive. Mutations in the homeobox-containing SHOX2 gene have been recently associated with early-onset and familial AF. Shox2 is a key regulator of sinus node development, and its deficiency leads to bradycardia...
Article
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Background: The enteric nervous system (ENS), a complex network of neurons and glial cells, coordinates major gastrointestinal functions. Impaired development or secondary aberrations cause severe enteric neuropathies. Neural crest-derived stem cells as well as enteric neuronal progenitor cells, which form enteric neurospheres, represent a promisi...
Conference Paper
Hirschsprung’s disease (HSCR), a congenital neurogastrointestinal disorder, is characterized by the loss of enteric ganglia (aganglionosis) in the colon. It has an oligogenic origin and is caused by functional impairment of neural crest and progenitor cells during embryonic development. Knowledge on underlying molecular and functional disturbances...
Article
Background The SHANK gene family encodes for postsynaptic scaffolding proteins with an important role at glutamatergic synapses in the brain and has been linked to a spectrum of neurodevelopmental disorders. The schizophrenia associated microRNA miR-137 and the SHANK genes converge on several levels, (a) both are expressed at the synapse, (b) both...
Article
Full-text available
Autism spectrum disorders (ASD) have a higher prevalence in male individuals compared to females, with a ratio of affected boys compared to girls of 4:1 for ASD and 11:1 for Asperger syndrome. Mutations in the SHANK genes (comprising SHANK1, SHANK2 and SHANK3) coding for postsynaptic scaffolding proteins have been tightly associated with ASD. As ea...
Article
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The SHANK scaffolding proteins are important organizers for signaling proteins in the postsynapse of excitatory neurons. The functional significance of SHANK proteins becomes apparent by the wide spectrum of neurodevelopmental and neuropsychiatric disorders associated with SHANK variants in human patients. A similar diversity of neuropsychiatric-li...
Article
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Height is a complex quantitative trait with a high heritability. Short stature is diagnosed when height is significantly below the average of the general population for that person's age and sex. We have recently found that the retinoic acid degrading enzyme CYP26C1 modifies SHOX deficiency phenotypes toward more severe clinical manifestations. Her...
Article
Full-text available
Background: Mutations in the SHANK genes, which encode postsynaptic scaffolding proteins, have been linked to a spectrum of neurodevelopmental disorders. The SHANK genes and the schizophrenia-associated microRNA-137 show convergence on several levels, as they are both expressed at the synapse, influence neuronal development, and have a strong link...
Data
Embryonic stem cells are pluripotent and have the capability to differentiate into almost all cell types of the body. Thus, they offer great potential for regenerative medicine such as cell-based therapies and basic research purposes including disease modeling and the elucidation of early developmental processes. In particular, this model system gi...
Article
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ARL13B encodes for the ADP-ribosylation factor-like 13B GTPase, which is required for normal cilia structure and Sonic hedgehog (Shh) signaling. Disruptions in cilia structure or function lead to a class of human disorders called ciliopathies. Joubert syndrome is characterized by a wide spectrum of symptoms, including a variable degree of intellect...
Article
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Irritable bowel syndrome (IBS) is a gut-brain disorder involving alterations in intestinal sensitivity and motility. Serotonin 5-HT4 receptors are promising candidates in IBS pathophysiology since they regulate gut motor function and stool consistency, and targeted 5-HT4R selective drug intervention has been proven beneficial in subgroups of patien...
Article
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PurposeCombined pituitary hormone deficiency (CPHD) is characterized by a malformed or underdeveloped pituitary gland resulting in an impaired pituitary hormone secretion. Several transcription factors have been described in its etiology, but defects in known genes account for only a small proportion of cases.Methods To identify novel genetic cause...
Article
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The elucidation of molecular mechanisms that restrict the potential of pluripotent stem cells and promote cardiac lineage differentiation is of crucial relevance, since embryonic stem cells (ESCs) hold great potential for cell based heart therapies. The homeodomain transcription factor Shox2 is essential for the development and proper function of t...
Article
Full-text available
The homeodomain transcription factor Shox2 controls the development and function of the native cardiac pacemaker, the sinoatrial node (SAN). Moreover, SHOX2 mutations have been associated with cardiac arrhythmias in humans. For detailed examination of Shox2-dependent developmental mechanisms in SAN cells, we established a murine embryonic stem cell...
Article
The postsynaptic scaffolding protein SHANK3 is essential for the normal function of glutamatergic synapses in the brain. Emerging evidence suggests that impaired plasticity of glutamatergic synapses contributes to the pathology of schizophrenia (SCZ). To investigate whether variants in the SHANK3 gene contribute to the etiology of SCZ, we sequenced...
Article
Full-text available
Autism and speech and language deficits are predominantly found in boys, however the causative mechanisms for this sex bias are unknown. Human FOXP1 is associated with autism, intellectual disability and speech and language deficits. Its closely related family member FOXP2 is involved in speech and language disorder and Foxp2 deficient mice have de...
Article
Full-text available
Objective Micro-RNAs (miRNAs) play a crucial role in controlling intestinal epithelial barrier function partly by modulating the expression of tight junction (TJ) proteins. We have previously shown differential messenger RNA (mRNA) expression correlated with ultrastructural abnormalities of the epithelial barrier in patients with diarrhoea-predomin...
Article
Background Men are more susceptible to neurodevelopmental diseases such as autism and language deficits than women however, the underlying factors remain unclear. FOXP1 is associated with autism, intellectual disability and speech and language deficits, while FOXP2 is exclusively involved in speech and language disorder. FOXP1 and FOXP2 together fo...