Biomedical subjects

Helga Rehder

Publications and source records attributed to Helga Rehder.

10 recordsLinked to original sources

PubMed2005

Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction, malformations and mental retardation (Johanson-Blizzard syndrome).

Johanson-Blizzard syndrome (OMIM 243800) is an autosomal recessive disorder that includes congenital exocrine pancreatic insufficiency, multiple malformations such as nasal wing aplasia, and frequent mental retardation. We mapped the disease-associated locus to chromosome 15q14-21.1 and identified mutations, mostly truncating ones, in the gene UBR1 in 12 unrelated families with Johanson-Blizzard syndrome. UBR1 encodes one of at least four functionally overlapping E3 ubiquitin ligases of the N-end rule pathway, a conserved proteolytic system whose substrates include proteins with destabilizing N-terminal residues. Pancreas of individuals with Johanson-Blizzard syndrome did not express UBR1 and had intrauterine-onset destructive pancreatitis. In addition, we found that Ubr1(-/-) mice, whose previously reported phenotypes include reduced weight and behavioral abnormalities, had an exocrine pancreatic insufficiency, with impaired stimulus-secretion coupling and increased susceptibility to pancreatic injury. Our findings indicate that deficiency of UBR1 perturbs the pancreas' acinar cells and other organs, presumably owing to metabolic stabilization of specific substrates of the N-end rule pathway.

Abnormalities, Multiple↗

PubMed2005

[Genetic counselling].

'Genetic counselling is the process by which patients or relatives at risk of a disorder that may be hereditary are advised of the consequences of the disorder, the probability of developing and transmitting it and of the ways in which this may be prevented or ameliorated.' The genetic counsellor will discuss the genetic basis and medical facts and also possible personal, familial, social and insurance implications of the respective disorder with the consultand. Further diagnostic investigations, such as genetic tests, may be helpful or necessary for risk predictions or may be required to reach a firm diagnosis. In asymptomatic individuals at risk for a late-onset genetic disorder genetic counselling is obligatory for predictive genetic testing. Genetic counselling also should be offered to symptomatic patients before a diagnostic test is performed. Thereby the patients might become aware in time about the personal, familial and social consequences of the test result that may exceed that of their actual illness. Due to medical confidentiality the geneticist is not allowed to contact other family members and to inform them about a familial disorder and warn them about their own genetic risk. This is the concern of the consultand. Various aspects make up genetic counselling as a specific process which concerns genetic diagnosis, risk estimation and accurate information on medical and genetic facts, but also has a supportive role ensuring that consultands may benefit from given advice and possible preventive measures.

Confidentiality↗

PubMed2005

[Genetic causes of mental retardation].

Mental retardation (MR) is defined as congenital or early onset lifelong impairment of cognitive and adaptive functioning (IQ < 70). It effects approximately 3% of the Western population. The causes are heterogenous. Numerical or structural chromosome abnormalities are responsible for 10-20% of the mild cases (MMR) and 40% of the severe cases (SMR). Among them Down syndrome represents the most frequent chromosome aberration and the most frequent defined MR syndrome. Gonosomal aberrations do not coincide with MR, as long as only one gonosome is lost or gained. Nearly all unbalanced structural autosomal aberrations cause SMR. Recent studies suggested that sub-microscopic chromosomal microdeletions or subtelomeric rearrangements account for approximately 10% of the undiagnosed cases. They represent a group of newly defined disorders. Single gene mutations are responsible for > 1200 known syndromal conditions with MR. But only few causative genes have been identified as yet. However, an increasing number of genes causing X-linked mental retardation (XLMR) have been localized and cloned, namely 38 genes of the 136 known syndromic conditions and 19 for the non-syndromic conditions. XLMR explains the 20 % excess of males over females. Despite the increasing knowledge about the causes of MR, about half of the cases remain undiagnosed. Guidelines for the diagnostic procedure in children with MR have been proposed.

Adolescent↗

PubMed2005

Situs ambiguus in a female fetus with balanced (X;21) translocation--evidence for functional nullisomy of the ZIC3 gene?

The human ZIC3 gene has been mapped to Xq26.2, the visceral heterotaxy locus HTX1, and has been shown to be mutated in X-linked situs ambiguus and/or complex heart defects. We report on a female fetus with situs ambiguus, asplenia and corrected transposition of the great arteries, displaying a (X;21) translocation. The balanced state of the t(X;21)(q26;p13) was verified by FISH on metaphase chromosomes of the fetus using DOP-PCR products of the microdissected der(21) and Xq-subtelomere specific sequences, and by PRINS with beta-satellite specific sequences. Examination with polymorphic markers flanking ZIC3 on DOP-PCR products of the microdissected der(21) chromosome evidenced that the complete copy of the ZIC3 gene was translocated to chromosome 21. Mutations in the fetal and parental ZIC3 genes were excluded by sequencing. Paternal origin of the der(X) and der(21) chromosomes was confirmed by use of polymorphic microsatellite markers from chromosome 21 and from the chromosomal region Xq26, respectively. X chromosome inactivation analysis using a PCR of a polymorphic (CAG)(n) repeat in the first exon of the androgen receptor gene showed a completely skewed X inactivation pattern with the paternal X as the active X chromosome, thus excluding functional disomy of distal Xq. A positional effect caused by the balanced (X;21) translocation may be responsible for functional nullisomy of ZIC3 and thus explain the situs and cardiac abnormalities in the fetus.

Chromosomes, Human, Pair 21↗

PubMed2003

BRCA2 germline mutations in familial pancreatic carcinoma.

BACKGROUND: Although as many as 10% of pancreatic cancer cases may have an inherited component, familial pancreatic cancer has not been linked to defects in any specific gene. Some studies have shown that families with germline mutations in the breast cancer susceptibility gene BRCA2 have an increased risk of breast and ovarian cancers, as well as a modestly increased risk of pancreatic cancer. To study these relationships in more detail, we examined whether BRCA2 germline mutations are associated with familial pancreatic cancer. METHODS: We identified 26 European families in which at least two first-degree relatives had a histologically confirmed diagnosis of pancreatic ductal adenocarcinoma. We sequenced genomic DNA isolated from peripheral blood lymphocytes obtained from participating family members to identify germline mutations in BRCA2. RESULTS: Three (12%, exact 95% confidence interval [CI] = 2% to 30%) families carried germline frameshift mutations in the BRCA2 gene that are predicted to result in a truncated BRCA2 protein. Two additional families harbored mutations previously designated as unclassified variants of BRCA2. Thus, 19% (exact 95% CI = 7% to 39%) of the families in our study had either a frameshift mutation or an unclassified variant of BRCA2. None of the families in our study met the criteria for familial breast or ovarian cancer. CONCLUSIONS: Our data support an important role for BRCA2 germline mutations in a subpopulation of families with familial pancreatic cancer. BRCA2 mutation analysis should be included in molecular genetic testing and counseling strategies in families with at least two first-degree relatives affected with ductal adenocarcinoma of the pancreas.

Adult↗

PubMed2003

Raine syndrome: report of a family with three affected sibs and further delineation of the syndrome.

We describe three affected sibs with Raine syndrome born to a consanguineous Turkish couple. Clinical findings and post-mortem assessment are presented. We have added previously unreported meso and severe telebrachyphalangy and urogenital anomalies to the clinical spectrum. Appositional new bone formation may be mistaken for fractures and callus formation--both prenatally by ultrasound and postnatally in radiographs. Further research is required to detect the underlying metabolic and molecular defects of this autosomal recessive syndrome.

Abnormalities, Multiple↗

PubMed2002

A patient severely affected by spinal neurofibromas carries a recurrent splice site mutation in the NF1 gene.

Spinal neurofibromas are found in up to 38% of NF1 patients. However, they cause clinical implications only in about 5% of the patients. In contrast, multiple symptomatic spinal neurofibromas are the main clinical finding in patients with familial spinal neurofibromatosis. Familial spinal neurofibromatosis has been considered to be a distinct clinical form of neurofibromatosis. Linkage analysis in two families and identification of a NF1 gene mutation in a third family strongly associate spinal neurofibromatosis with the NF1 gene. We describe a NF1 patient who satisfies the NIH diagnostic criteria and has severe spinal involvement with bilateral spinal root neurofibromas at every level. A recurrent splice site mutation (IVS19b-3C>G) was identified in the NF1 gene in the patient. We discuss the possibility that the clinical picture of this patient represents an additional example of spinal neurofibromatosis. By comparison of the clinical expression of NF1 in this patient and that in another patient with the identical mutation the hypothesis that spinal neurofibromatosis is associated with a particular mutation is highly unlikely. The involvement of other genes linked to the NF1 gene or modifying genes is currently the most likely explanation for the clinical phenotype of spinal neurofibromatosis.

Adult↗

PubMed2002

[Familial pancreatic cancer--concept for study of the National Case Collection and early diagnosis program for high risk people].

Ductal pancreatic cancer is a public health problem on the increase. The lethality and incidence of this disease are almost identical. A number of these cancers cluster in families. By definition, pancreatic cancer appearing in at least two first degree relatives is named familial pancreatic cancer (FPC). The "National Case Collection Familial Pancreatic Cancer" (FaPaCa) was founded at the Philipps University of Marburg, Germany, in July 1999 within the scope of the project "Clinical and genetic examinations of familial exocrine pancreatic cancer including the foundation of a national case collection" (http://www.med.uni-marburg.de/fapaca). The aims of this project are 1 to evaluate the share of FPC of all pancreatic cancers by performing a multi-centered study, 2 to identify epidemiological risk factors that predispose to pancreatic cancer in these families, 3 to identify families with a likely genetic predisposition to pancreatic cancer, 4 to offer a screening program for high risk individuals in these families, which is to be evaluated in an observational study, and finally to identify presumed genetic defects that predispose to pancreatic cancer in FPC families. This manuscript presents the scientific concept behind the FaPaCa project and reports on its attendant screening program for FPC families.

Germany↗

PubMed2001

Neuropathology of Raine syndrome.

We present three cases of Raine syndrome occurring in siblings of consanguineous parents. Raine syndrome is characterised by generalised osteosclerosis with craniofacial anomalies and intracranial calcifications. So far, only nine cases have been reported, and no evaluation of the distribution and extent of the cerebral mineralisations, as well as their impact on the surrounding tissue, has been undertaken yet. In our cases, calcifications were unevenly distributed throughout the central nervous system, not associated with neuronal loss or dystrophic events and appeared mostly as single calcospherites within the neuropil with occasional confluent deposits at advanced gestational age. There was intense perifocal microgliosis around single immature calcospherites, as well as mild astrogliosis around and within the confluent lesions, in which occasional macrophages could be found. Rarely, mineralisations occurred in blood-vessel walls, mainly affecting basal ganglia. Preferential sites of calcification were parietal and occipital periventricular white matter and corpus callosum, while frontal lobes were mildly affected. The cortex, temporal lobes as well as internal capsule, brain stem, cerebellum, leptomeninges, pituitary gland and choroid plexus were devoid of mineralisations. The subcortical grey matter was moderately involved in the putamen and pallidum, mildly in the caudate nucleus and subependymal germ cell matrix and not at all in the thalamus, Ammon's horn, amygdala and substantia nigra. The distribution of mineral deposits was thus inversely correlated to regional blood circulation and capillary density, with calcifications being concentrated in more sparsely perfused areas but lacking in highly vascularised tissue. This inverse relationship between mineralisation and regional blood flow was reflected in the varying distribution of calcospherites in grey and white matter as well as in the white matter of different lobes.

Brain Diseases↗

PubMedDate not supplied

Clinical, cytogenetic and molecular investigation in a fetus with Wolf-Hirschhorn syndrome with paternally derived 4p deletion. Case report and review of the literature.

Wolf-Hirschhorn (4p-) syndrome (WHS), caused by partial deletion of the short arm of chromosome 4, has been extensively described in children and young adults. Knowledge on fetuses with WHS is still limited due to the small number of published cases. We report on a fetus with prenatally diagnosed severe intrauterine growth retardation, reduced thoracal diameter, clubfeet deformity and midface hypoplasia including slight microretrognathia indicative for fetal karyotyping. Chromosome analysis after amniocentesis revealed a de novo terminal deletion of chromosome 4p [karyotype: 46,XX,del(4) (p16)] which was confirmed by FISH. Analyses of a set of polymorphic markers mapping in 4pter->4p15.3 showed absence of paternal haplotypes. These observations corroborate the preferential paternal origin of the de novo 4p deletion in WHS patients. Furthermore, the distal breakpoint could be narrowed to band 4p16.1. At autopsy, the fetus showed typical craniofacial dysmorphic signs of WHS, severe IUGR and delayed bone age. This report suggests the possibility of recognising the particular phenotype of WHS in utero by prenatal ultrasound and emphasises the importance of karyotyping fetuses with severe IUGR, especially when the amount of amniotic fluid is normal.

Abnormalities, Multiple↗