Biomedical subjects

Beate Niesler

Publications and source records attributed to Beate Niesler.

9 recordsLinked to original sources

PubMed2006

Genotypes and phenotypes in children with short stature: clinical indicators of SHOX haploinsufficiency.

BACKGROUND: Short stature affects approximately 2% of children, representing one of the more frequent disorders for which clinical attention is sought during childhood. Despite assumed genetic heterogeneity, mutations or deletions of the short stature homeobox-containing gene (SHOX) are found quite frequently in subjects with short stature. Haploinsufficiency of the SHOX gene causes short stature with highly variable clinical severity, ranging from isolated short stature without dysmorphic features to Léri-Weill syndrome, and with no functional copy of the SHOX gene, Langer syndrome. METHODS: To characterise the clinical and molecular spectrum of SHOX deficiency in childhood we assessed the association between genotype and phenotype in a large cohort of children of short stature from 14 countries. RESULTS: Screening of 1608 unrelated individuals with sporadic or familial short stature revealed SHOX mutations or deletions in 68 individuals (4.2%): complete deletions in 48 (70.6%), partial deletions in 4 (5.9%) and point mutations in 16 individuals (23.5%). Although mean height standard deviation score (SDS) was not different between participants of short stature with or without identified SHOX gene defects (-2.6 vs -2.6), detailed examination revealed that certain bone deformities and dysmorphic signs, such as short forearm and lower leg, cubitus valgus, Madelung deformity, high-arched palate and muscular hypertrophy, differed markedly between participants with or without SHOX gene defects (p<0.001). Phenotypic data were also compared for 33 children with Turner syndrome in whom haploinsufficiency of SHOX is thought to be responsible for the height deficit. CONCLUSION: A phenotype scoring system was developed that could assist in identifying the most appropriate subjects for SHOX testing. This study offers a detailed genotype-phenotype analysis in a large cohort of children of short stature, and provides quantitative clinical guidelines for testing of the SHOX gene.

Abnormalities, Multiple↗

PubMed2005

Mutational analysis of the PITX2 coding region revealed no common cause for transposition of the great arteries (dTGA).

BACKGROUND: PITX2 is a bicoid-related homeodomain transcription factor that plays an important role in asymmetric cardiogenesis. Loss of function experiments in mice cause severe heart malformations, including transposition of the great arteries (TGA). TGA accounts for 5-7% of all congenital heart diseases affecting 0.2 per 1000 live births, thereby representing the most frequent cyanotic heart defect diagnosed in the neonatal period. METHODS: To address whether altered PITX2 function could also contribute to the formation of dTGA in humans, we screened 96 patients with dTGA by means of dHPLC and direct sequencing for mutations within the PITX2 gene. RESULTS: Several SNPs could be detected, but no stop or frame shift mutation. In particular, we found seven intronic and UTR variants, two silent mutations and two polymorphisms within the coding region. CONCLUSION: As most sequence variants were also found in controls we conclude that mutations in PITX2 are not a common cause of dTGA.

Alternative Splicing↗

PubMed2005

Alteration of DNA binding, dimerization, and nuclear translocation of SHOX homeodomain mutations identified in idiopathic short stature and Leri-Weill dyschondrosteosis.

Haploinsufficiency of the short stature homeobox gene SHOX has been found in patients with idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis (LWD). In addition to complete gene deletions and nonsense mutations, several missense mutations have been identified in both patient groups, leading to amino acid substitutions in the SHOX protein. The majority of missense mutations were found to accumulate in the region encoding the highly conserved homeodomain of the paired-like type. In this report, we investigated nine different amino acid exchanges in the homeodomain of SHOX patients with ISS and LWD. We were able show that these mutations cause an alteration of the biological function of SHOX by loss of DNA binding, reduced dimerization ability, and/or impaired nuclear translocation. Additionally, one of the mutations (c.458G>T, p.R153L) is defective in transcriptional activation even though it is still able to bind to DNA, dimerize, and translocate to the nucleus. Thus, we demonstrate that single missense mutations in the homeodomain fundamentally impair SHOX key functions, thereby leading to the phenotype observed in patients with LWD and ISS.

Active Transport, Cell Nucleus↗

PubMed2005

Serotonin receptor genes HTR3A and HTR3B are not involved in Gilles de la Tourette syndrome.

Serotonin has been implicated in a variety of neuropsychiatric disorders. Serotonergic dysfunction is thought to be involved in the pathophysiology of the Gilles de la Tourette Syndrome (GTS). GTS is characterized by multiple vocal and motoric tics. Among selective, competitive 5-HT(3) receptor antagonists, ondansetron represents a promising drug in GTS treatment. In our study both serotonin receptor subunit genes, HTR3A and HTR3B, were examined for sequence variations in GTS patients. We have analyzed DNA samples from 49 patients by SSCP and dHPLC. In HTR3A, we detected five mutations and in HTR3B the analysis revealed six sequence variants. Statistical analysis rated all variants as probably non-disease-related polymorphisms. Yet a certain effect of the detected variants on the severity of the disease cannot be excluded.

Base Sequence↗

PubMed2004

Investigation of the human serotonin receptor gene HTR3B in bipolar affective and schizophrenic patients.

The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) mediates a multitude of central nervous functions by activating 5-HT receptor subtypes. A dysfunction of serotonergic neurotransmission is considered to play a major role in the pathophysiology of complex neuropsychiatric disorders. In our study, a mutation screen of the serotonin receptor gene HTR3B was carried out to explore a putative contribution to the etiology of bipolar affective disorder (BPAD) and schizophrenia (SZ). Screening of 49 patients suffering from BPAD, 78 patients with SZ and 62 control individuals revealed eleven sequence variations including a 3 bp deletion within the 5'UTR (5' untranslated region), four exonic and five intronic SNPs as well as a point mutation in the 3'UTR of HTR3B. Four of these sequence variations have not been described previously. Statistical computation rated most variants as probably non-disease related polymorphisms. However, IVS6 + 31C > T, IVS6 + 40C > A, and 1386T > C were solely detected in bipolar affective patients and in none of the controls. Interestingly, we observed a significant underrepresentation of the 3 bp deletion -100_-102delAAG in an extended sample of 162 bipolar affected patients compared to controls (allele-wise: 8% vs. 15%, P = 0.006, OR = 0.49, 95% CI: 0.3-0.82; genotype-wise: 15,5% vs. 29,0%, P = 0.005, OR = 0.45, 95% CI: 0.26-0.77). We suggest that this deletion may influence translational efficiency, thereby possibly affecting the development of bipolar affective disease.

5' Untranslated Regions↗

PubMed2004

Mutational analysis of serotonin receptor genes: HTR3A and HTR3B in fibromyalgia patients.

The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has been implicated in numerous human disorders. Dysfunction of serotonergic neurotransmission is thought to play a major role in the pathophysiology of the fibromyalgia syndrome (FMS) which is characterised by non-restorative sleep and severe pain. In our study, both serotonin receptor subunit genes, HTR3A and HTR3B, have been investigated for sequence variations in FMS patients in order to reveal a possible involvement in the aetiology of FMS. We examined DNA samples from 48 patients with FMS representing sporadic cases by single-strand conformation polymorphism (SSCP) and denaturing high-performance liquid chromatography (dHPLC) analysis, sequenced samples with conspicuous patterns and performed statistical calculations. HTR3A mutational analysis revealed one novel as well as five known sequence variations. Investigating HTR3B, we detected seven formerly described mutations and one novel sequence variant. Statistical computation rated all variants as probably non-disease-related polymorphisms. Nevertheless, one might speculate about an effect of the respective sequence variants on the severity of the disease. Sequence variants of the serotonin receptor subunit genes HTR3A and HTR3B indicate no obvious significance in the aetiology of fibromyalgia, yet they represent the basis for future studies on their pharmacogenetic relevance.

Chromatography, High Pressure Liquid↗

PubMed2003

Cloning, physical mapping and expression analysis of the human 5-HT3 serotonin receptor-like genes HTR3C, HTR3D and HTR3E.

For more than 50 years the serotonin system has been the subject of intense research. This has provided an exciting insight and led to the discovery of multiple drugs targeting serotonin receptors, metabolising enzymes and re-uptake sites. During the past few years researchers focussed especially on elucidating the complexity of different physiological actions in the serotonergic network. We have identified two novel human serotonin 5-hydroxytryptamine type 3 receptor-like genes, HTR3D and HTR3E, by performing homology searches using the public human sequence databases and subsequently cloned the full length cDNAs by 5' and 3' rapid amplification of complementary DNA ends. Mapping of HTR3D and HTR3E by hybridisation, polymerase chain reaction and fluorescence in situ hybridisation revealed that both genes together with HTR3C are clustered in a subinterval of less than 100 kb on chromosome 3q27. Comparative expression analysis of all HTR3 genes, namely HTR3A, B, C, D and E showed HTR3D expression to be restricted to kidney, colon and liver and HTR3E expression to colon and intestine, whereas all other genes are widely expressed in many tissues including brain.

Amino Acid Sequence↗

PubMed2002

The human SHOX mutation database.

The human SHOX database has recently been established to provide clinicians and scientists access to a central source of information about all known SHOX mutations associated with short stature phenotypes such as idiopathic short stature, Lèri-Weill dyschondrosteosis, Langer syndrome, and Turner syndrome. So far, the database contains 29 unique intragenic mutations of the SHOX gene. These mutations were detected in a total of 39 patients from different families. Fourteen of these mutations have been found from the SHOX research group at the Institute of Human Genetics in Heidelberg, Germany; 25 mutations are from data reported in the literature. Not included in this database are complete SHOX gene deletions which represent the majority of all detectable SHOX mutations [Rappold et al., 2002]. The database is accessible via the website www.shox.uni-hd.de. It contains general information about the SHOX gene, and allows remote users to search the data and to submit new mutations to the database.

Base Sequence↗

PubMed2002

Deletions of the homeobox gene SHOX (short stature homeobox) are an important cause of growth failure in children with short stature.

Short stature, with an incidence of 3 in 100, is a fairly frequent disorder in children. Idiopathic short stature refers to patients who are short due to various unknown reasons. Mutations of a human homeobox gene, SHOX (short stature homeobox), have recently been shown to be associated with the short stature phenotype in patients with Turner syndrome and most patients with Léri-Weill dyschondrosteosis. This study addresses the question of the incidence and type of SHOX mutations in patients with short stature. We analyzed the SHOX gene for intragenic mutations by single strand conformation polymorphism, followed by sequencing, in 750 patients and for complete gene deletions by fluorescence in situ hybridization in 150 patients (total, 900 patients). This is the largest group of patients with short stature studied to date for SHOX mutations. All patients had a normal karyotype, and their height for chronological age were below the third percentile or minus 2 SD of national height standards. All were without obvious skeletal features reminiscent of the Leri-Weill syndrome at the time of diagnosis. Silent, missense, and nonsense mutations and a small deletion in the coding region of SHOX were identified in 9 of the 750 patients analyzed for intragenic mutations. Complete gene deletions were detected in 3 of the 150 patients studied for gene deletions. At least 3 of the 9 intragenic mutations were judged to be functional based upon the genotype- phenotype relationship for the parents and normal control individuals. We conclude that SHOX mutations have been detected in 2.4% of children with short stature. The spectrum of SHOX mutations is biased, with the vast majority leading to complete gene deletions. The prevalence of short stature due to SHOX gene mutations among children with short stature appears to be similar to that of GH deficiency or Turner syndrome. Family studies of the children with SHOX mutations often reveal older family members with same mutation who exhibit mild skeletal features reminiscent of the Turner syndrome, such as high-arched palate, short neck, abnormal auricular development, cubitus valgus, genu valgum, short fourth metacarpals, and Madelung deformity.

Adolescent↗