[Cancer-associated genodermatoses]. / Tumorassoziierte Genodermatosen.

Hereditary tumor syndromes are characterized by a familial occurrence of tumors/cancer. A hereditary tumor syndrome should be suspected if a familial occurrence of cancer is seen and/or persons at younger age are affected. Some of the currently known tumor syndromes are associated with specific skin symptoms that can aid the physician in establishing the correct diagnosis. Examples are fibrofolliculoma in Birt-Hogg-Dubé syndrome, epidermal cysts, sebaceous cysts, neurofibroma in Gardner syndrome and sebaceous neoplasms or keratoacanthoma in Muir-Torre syndrome. If a genetic tumor syndrome is suspected, genetic testing and counselling should be performed in the index patient and is also recommended for family members. Affected patients should be offered regular clinical surveillance by the appropriate medical disciplines. Since curative therapy does not exist so far, preventive screening is of great importance.

Delayed diagnosis of Birt-Hogg-Dubé syndrome due to marked intrafamilial clinical variability: a case report.

BACKGROUND: Birt-Hogg-Dubé syndrome is a genetic syndrome caused by mutations in the FLCN gene. The main symptoms are lung bullae and pneumothorax, benign and malignant kidney tumors, and facial fibrofolliculoma. The risk of pneumothorax is considerable between ages 20-40 years, but decreases markedly after this age range and first-time pneumothorax after age 50 years is rare. Fibrofolliculomas usually occur between ages 35 and 45 years, while the risk for kidney cancer increases steadily with age, starting in young adulthood. However, we demonstrate here that within the same family patients might develop symptoms significantly before or after the usual age range, obscuring the typical clinical pattern and delaying diagnosis. CASE PRESENTATION: The 43 year old index patient had a history of lung bullae and recurrent pneumothoraces starting 14 years earlier. His father (age 83 years) and one of the paternal uncles experienced their first pneumothorax unusually late after the age of 60 years. The uncle subsequently had four more pneumothoraces, and was diagnosed with kidney in his early 70s. Considerable differences in age of onset were also observed with regard to facial fibrofolliculomas that both paternal uncles developed very early around age 20 years, but which the father only started to show in his eighth decade. Birt-Hogg-Dubé syndrome was finally diagnosed when the index patient started to develop fibrofolliculomas within the typical age range. CONCLUSIONS: The family described here illustrates that Birt-Hogg-Dubé syndrome can be difficult to recognize, if presenting with considerable intrafamilial clinical variability. With a life-time kidney cancer risk of about 14-35% the consequences of delayed diagnosis might be grave for the affected family members. The possibility of Birt-Hogg-Dubé syndrome should therefore be taken into consideration in apparently sporadic patients presenting with lung bullae and pneumothorax.

A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy.

Epilepsy affects at least 2% of the population at some time in their lives. The epilepsies are a heterogeneous group of disorders, many with an inherited component. Although specific genes have been identified in a few rare diseases causing seizures as part of a more diffuse brain disorder, the molecular pathology of the common idiopathic epilepsies is still unknown. Linkage has been reported for some generalised epilepsy syndromes, but only very recently for familial partial epilepsy syndromes. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a partial epilepsy causing frequent, violent, brief seizures at night, usually beginning in childhood. The gene for ADNFLE maps to chromosome 20q13.2-q13.3 in one large Australian kindred. The neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) maps to the same region of 20q (ref. 12) and the gene is expressed in all layers of the frontal cortex. We screened affected family members for mutations within CHRNA4 and found a missense mutation that replaces serine with phenylalanine at codon 248, a strongly conserved amino acid residue in the second transmembrane domain. The mutation is present in all 21 available affected family members and in four obligate carriers, but not in 333 healthy control subjects.

A potassium channel mutation in neonatal human epilepsy.

Benign familial neonatal convulsions (BFNC) is an autosomal dominant epilepsy of infancy, with loci mapped to human chromosomes 20q13.3 and 8q24. By positional cloning, a potassium channel gene (KCNQ2) located on 20q13.3 was isolated and found to be expressed in brain. Expression of KCNQ2 in frog (Xenopus laevis) oocytes led to potassium-selective currents that activated slowly with depolarization. In a large pedigree with BFNC, a five-base pair insertion would delete more than 300 amino acids from the KCNQ2 carboxyl terminus. Expression of the mutant channel did not yield measurable currents. Thus, impairment of potassium-dependent repolarization is likely to cause this age-specific epileptic syndrome.

Ion channels and epilepsy in man and mouse.

Inherited disorders of voltage-gated ion channels are a recently recognized etiology of epilepsy in the developing and mature central nervous system. Two human epilepsy syndromes, benign familial neonatal convulsions and generalized epilepsy with febrile seizures plus, represent K+ and Na+ channelopathies, and other newly defined syndromes have now been mapped to chromosomal regions that are rich in ion channel genes. Experimental mouse models promise a resolution of their intriguing pathophysiology, which includes a diverse array of cellular phenotypes consistent with the differential contributions of individual channels to excitability in neural networks.

Compound heterozygosity for three common MEFV mutations in a highly consanguineous family with familial Mediterranean fever.

Consanguinity is not the only factor influencing the occurrence of autosomal recessive disorders such as familial Mediterranean fever (FMF). The extended, multiple consanguineous Turkish pedigree presented here demonstrates that the population frequency of certain mutations (so-called "ancient" mutations) can be at least equally important. In high-risk populations different combinations of mutations can occur within the same family, increasing not only the intrafamilial clinical variability, but also causing considerable recurrence risks even in marriages with unrelated spouses.

Benign familial neonatal convulsions: always benign?

BACKGROUND: Benign familial neonatal convulsions (BFNC) is a rare autosomal dominant seizure disorder usually described to be characterized by a benign course, spontaneous remission and normal psychomotor development. The latter statement had come under consideration when a few case reports of families with less than favorable outcomes were published. METHODS: Since 1998 a total of 112 families suspected to have BFNC have been referred to our lab for genetic testing. Within this sample we identified private KCNQ2 mutations in 17 BFNC families. For 10 of those 17 families follow up information about the psychomotor development and the outcome were available. RESULTS: In 4 (40%) of the 10 families at least 1 affected individual showed delayed psychomotor development or mental retardation. Three of the four mutations were familial, while the fourth mutation was de novo. Mutations associated with an unfavorable outcome tended to be located within the functionally critical S5/S6 regions of the KCNQ2 gene. CONCLUSIONS: Our data raise the question if BFNC can indeed be described as a benign disorder, and which are the genetic and/or environmental factors that influence the outcome.

Upstream open reading frames regulate cannabinoid receptor 1 expression under baseline conditions and during cellular stress.

The cannabinoid receptor subtype 1 gene CNR1 is not only associated with phenotypes such as cognitive performance, addiction and anxiety, but is also known to be crucially involved in responses to acute and chronic psychological and cellular stress conditions. Functional analysis of the 5' untranslated regions of the five known mRNA variants of the human CNR1 gene revealed that two of these variants contain upstream open reading frames that are able to modulate gene expression both under baseline condition and conditions of cellular stress including hypoxia, glucose restriction and hyperthermia. The upstream open reading frames might provide a mechanism that enables the cannabinoid 1 receptor to escape the general repression of protein synthesis that is typical for conditions of cellular stress.

Classical Alzheimer features and cholinergic dysfunction: towards a unifying hypothesis?

OBJECTIVE: Our autopsy studies show possible links between classical Alzheimer pathology and decreased expression of nicotinic acetylcholine receptors. For further elucidation we are now using in vitro models. We report preliminary evidence for the impact of beta-amyloid on nicotinic receptor expression in hippocampal dissociation culture. METHODS: Cultures (E18 rats) were grown in a serum-free medium and incubated at 8 days in vitro for 3 days with 1 microM Abeta1-42. Expression of alpha4, alpha7, and beta2 nicotinic receptor subunit protein was assessed immunohistochemically and rated semiquantitatively. RESULTS: Abeta1-42 incubation resulted in a massive reduction of alpha4 protein-expressing neurons, this effect was less pronounced for the alpha7 and beta2 subunit protein. CONCLUSION: These findings provide first evidence for a direct impact of classical Alzheimer pathology features on nicotinic receptor expression in vitro. Our model will be useful for testing the potential of drugs to stop or reverse these effects.

Properties of neuronal nicotinic acetylcholine receptor mutants from humans suffering from autosomal dominant nocturnal frontal lobe epilepsy.

1. Physiological and pharmacological properties of the human neuronal alpha4beta2 nicotinic AChR and mutants found in patients suffering from autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) were studied. 2. Investigations of nicotinic AChRs reconstituted in Xenopus oocytes with the control or mutated alpha4 subunits revealed that both mutation S248F as well as the Leucine insertion (776ins3) result in major but different changes in the physiological and pharmacological properties of the receptors. 3. Mutation S248F causes a decrease in apparent affinity to ACh of about 7 fold. In addition, this receptor already desensitizes during exposure to agonist concentration 3000 times lower than the control. 4. 776ins3 provokes a 10 fold increase of apparent ACh affinity, an increase in the IC50 caused by prolonged ACh exposures and a slowing down of the response decay. 5. At saturating ACh concentration cells expressing the S248F mutant display average currents that are about five times smaller than control. 6. When measured at very low concentration, agonist sensitivities of the control and mutated receptors to ACh, nicotine and epibatidine exhibit differences that match those observed for higher agonist concentrations. 7. Mutation 776ins3 increases the apparent efficacy to cytisine. 8. Data presented herein suggest that mutation S248F mainly affects the desensitization properties of the receptor while the leucine insertion (776ins3) increases the probability of transition to the active state. Although these mutations differentially affect the receptor properties they both result in reduced permeability to calcium and enhanced desensitization sensitivity that might account for the ADNFLE phenotype.

Genes and mutations in idiopathic epilepsy.

Partial or generalized idiopathic epilepsies, which account for up to 40% of all epilepsies, are characterized by a mostly benign course and no apparent etiology other than a genetic predisposition. So far, the genetic defects underlying three different idiopathic epilepsy syndromes have been identified: mutations in the CHRNA4- or CHRNB subunits of the neuronal nicotinic acetylcholine receptor are found in familial nocturnal frontal lobe epilepsy, while defects in the voltage-gated potassium channels KCNQ2 and KCNQ3 have recently been identified in benign familial neonatal convulsions. The syndrome of "generalized epilepsy with febrile seizures plus" can be caused by mutations affecting the voltage-gated sodium channel subunits SCN1B and SCN1A or the gamma 2-subunit of the GABA(A) receptor. The results of recent molecular studies contributed largely to our understanding of the etiology and pathophysiology of idiopathic epilepsies.

Mutation analysis of the inwardly rectifying K(+) channels KCNJ6 (GIRK2) and KCNJ3 (GIRK1) in juvenile myoclonic epilepsy.

Genetic factors play a major role in the etiology of idiopathic generalized epilepsy. However, in most syndromes, especially the common ones, multiple genetic factors seem to be involved. Mutations in K(+) channel genes have previously found to be associated with epilepsy both in humans and in mice. The weaver mice phenotype, characterized by ataxia, tremor, male infertility, and tonic-clonic seizures, is caused by a point mutation in the inwardly rectifier K(+) channel gene KCNJ6 (GIRK2). A knockout mouse model deprived of functional KCNJ6 protein is susceptible to spontaneous and provoked seizures without showing the histological signs of neuronal cell death found in the weaver mouse. Thus, the KCNJ6 gene seems to play an important role in seizure control. We therefore performed a mutation analysis of KCNJ6 and the related KCNJ3 gene in 38 patients with juvenile myoclonic epilepsy (JME). Two novel same-sense nucleotide exchanges were identified, but none of these changed the coding sequence. These results do not support a major role for the KCNJ6/KCNJ3 heteromeric receptor in the etiology of JME. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:8-11, 2000

Neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) and panic disorder: an association study.

Anxiety disorders have been reported to be associated with low-voltage EEG (LVEEG). Some cases with LVEEG (approximately 1/3) have been linked to chromosome 20q13.2q13.3. In the same chromosomal region, the gene for the neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) has been located. We therefore tested the hypothesis that polymorphisms in the CHRNA4 gene show an allelic association with panic disorder. We examined the allele frequencies of three different CHRNA4 polymorphisms in patients with panic disorder and in healthy controls. No significant differences in the allele frequencies of these three polymorphisms were noted. This study does not support an association between panic disorder and the CHRNA4 gene.

The new voltage gated potassium channel KCNQ5 and neonatal convulsions.

In 1998, mutations in the voltage gated potassium channel gene KCNQ2 were found to be the main cause underlying the autosomal dominant inherited syndrome of benign familial neonatal convulsions (BFNC). In one BFNC family a mutation was found in an homologous gene, KCNQ3. We have now identified another brain-expressed member of this ion channel subfamily, KCNQ5, which maps to chromosome 6q14. On the genomic level KCNQ5 is composed of 14 exons, which are coding for 897 amino acid residues. Mutation analysis made KCNQ5 unlikely as a candidate gene for benign neonatal convulsions in patients with a positive family history for neonatal or early infantile seizures, but without mutations in the KCNQ2 or KCNQ3 genes.

Cloning and mutation analysis of the human potassium channel KCNQ2 gene promoter.

Benign familial neonatal convulsions (BFNC) have been previously found to be associated with mutations within the coding region of KCNQ2. We have now cloned and analyzed the promoter region of the human KCNQ2 gene. 5'-RACE identified a transcription start site (TSS) located 200 bp upstream of the ATG start codon. The TSS is located close to a repetitive region containing seven copies of a degenerate 42-mer repeat. Several different luciferase (LUC) reporter plas- mids containing fragments from the KCNQ2 5'-flanking region were constructed and expressed in NT2N and SH-SY5Y cell lines. A core promoter region was found to be located between bp 20 and bp 74 upstream of the TSS. Neither the promoter region nor the repetitive region showed any mutations in 13 index patients from unrelated BFNC families.

The voltage gated potassium channel KCNQ2 and idiopathic generalized epilepsy.

Mutations in the voltage gated potassium channel gene KCNQ2 and the homologous gene KCNQ3 have been found to cause a rare monogenic subtype of idiopathic generalized epilepsy, the benign familial neonatal convulsions. Recently, the heteromeric KCNQ2/KCNQ3 channel was found to contribute to the native M-current, one of the most important regulators of neuronal excitability. By performing a systematic mutation scan of the coding region and an association study involving a frequent Thr752Asn substitution polymorphism, we, therefore, investigated whether allelic variation of the KCNQ2 gene confers susceptibility to common subtypes of idiopathic generalized epilepsy. Our results do not provide evidence that allelic variation of the KCNQ2 gene contributes a common and relevant effect to the pathogenesis of common subtypes of idiopathic generalized epilepsy.

Mutation screening of the CHRNA4 and CHRNB2 nicotinic cholinergic receptor genes in Alzheimer's disease.

Potential genomic changes leading to decreased nicotine binding, crucial for cognitive dysfunction in Alzheimer's disease (AD), have not yet been studied. A search for mutations of the genes coding for the most widely distributed nicotinic receptor subtype alpha4beta2 (CHRNA4/CHRNB2) has been performed in AD patients by screening the coding regions of both genes by single strand conformation analysis and heteroduplex analysis of fibroblast-derived genomic DNA. Polymorphisms in CHRNA4, none of which led to amino acid changes in the predicted sequence, were found in three patients. Although the other receptor subunits have yet to be screened, it appears likely that the reduction of nicotine binding sites in AD is not due to genomic changes.

Expression of nicotinic acetylcholine receptors in Alzheimer's disease: postmortem investigations and experimental approaches.

Nicotinic ligand binding studies have shown rather early that the cholinoceptive system is affected in Alzheimer's disease (AD). Today, molecular histochemistry enables one to study the nicotinic acetylcholine receptor (nAChR) subunit expression on the cellular level in human autopsy brains, in animal models and in in vitro approaches, thus deciphering the distribution of nAChRs and their role as potential therapeutic targets. The studies on the nAChR expression in the frontal and temporal cortex of AD patients and age-matched controls could demonstrate that both, the numbers of alpha4- and alpha7-immunoreactive neurons and the quantitative amount, in particular of the alpha4 protein, were markedly decreased in AD. Because the number of the corresponding mRNA expressing neurons was unchanged these findings point to a translational/posttranslational rather than a transcriptional event as an underlying cause. This assumption is supported by direct mutation screening of the CHRNA4 gene which showed no functionally important mutations. To get more insight into the underlying mechanisms, two model systems organotypic culture and primary hippocampal culture - have been established, both allowing to mimic nAChR expression in vitro. In ongoing studies the possible impact of beta-amyloid (Abeta) on nAChR expression is tested. Preliminary results obtained from primary cultures point to an impaired nAChR expression following Abeta exposure.

Neuronal nicotinic receptors in human epilepsy.

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a rare monogenic idiopathic partial epilepsy characterized by clusters of frontal lobe motor seizures during sleep. Recently, it has been shown that mutations of the chromosome-20q-located neuronal nicotinic acetylcholine receptor alpha4-subunit (CHRNA4) are associated with ADNFLE in some families, but that other families are not linked to this locus. Both CHRNA4 mutations (Ser248Phe and 776ins3) identified so far are found in the pore-forming second transmembrane region of the gene. Electrophysiological studies showed that mutations in this functional important part of the receptor subunit have a profound effect on the permeability for calcium ions. Interestingly, the Ser248Phe mutation was found again in a second ADNFLE family. Haplotype analysis excluded a founder effect and showed that Ser248Phe occurred independently twice. This provides the possibility to study the effect of the same mutation on different genetic backgrounds. Several attempts have been made to identify additional genes responsible for ADNFLE. But despite some positive linkage results including the CHRNA3-CHRNA5-CHRNB2 cluster on chromosome 15q24, no further mutations have been found so far. The mutation screening of functionally important parts of CHRNA5 in 12 ADNFLE patients did not support a causative role of this nicotinic acetylcholine receptor subunit.