Identification of the genetic locus for keratosis palmaris et plantaris on chromosome 17 near the RARA and keratin type I genes.

Familial keratosis palmaris et plantaris (KPPF) is characterized by extreme keratinization and desquamation of the skin of the palmar and plantar surfaces of the hands and feet. We have mapped the causative genetic defect to an 8 cM interval on 17q12-24 in or close to the acidic keratin (type I) gene cluster. We show that KPPF co-segregates with a rare, high molecular weight allele of an insertion-deletion polymorphism in the C-terminal coding region of the keratin 10 gene (Z = 8.36 at theta = 0.00) and segrates as a true autosomal dominant trait. Some pedigrees with familial hyperkeratosis of the palms and soles have co-inherited diseases such as congenital malformations and familial cancers. Our analysis provide a region which should be investigated for contiguous gene syndromes in such pedigrees.

Association between angiotensin-converting enzyme and Alzheimer disease.

BACKGROUND: Angiotensin-converting enzyme has been reported to show altered activity in patients with neurologic diseases. An insertion-deletion polymorphism in ACE has recently been linked to heart disease, cerebrovascular disease, and AD. OBJECTIVE: To determine whether the angiotensin-converting enzyme (ACE) is associated with risk of Alzheimer disease (AD). METHODS: We investigated the ACE polymorphism as a potential risk factor for AD in 151 patients with AD and 206 ethnically matched controls from Russia and in 236 patients with AD and 169 controls from North America by means of allele association methods and logistic regression. RESULTS: None of the ACE genotypes was associated with increased susceptibility to AD in the total sample or in subsets stratified by apolipoprotein E gene (APOE) epsilon4 status. However, the D allele was more frequent among AD cases between ages 66 and 70 years compared with controls in both the Russian (P = .02) and North American (P = .001) datasets. In this age group, the effect of D (odds ratio, 11.2; 95% confidence interval, 2.9-44.0) appeared to be independent of and equal or greater in magnitude to the effect of APOE epsilon4 (odds ratio, 7.8; 95% confidence interval, 3.5-7.4). CONCLUSIONS: Our results suggest that APOE and ACE genotypes may be independent risk factors for late-onset AD, but the ACE association needs to be confirmed in independent samples in which the time and extent of vascular cofactors can be assessed.

Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations.

BACKGROUND: Mutations in the presenilin-1 gene (PS1) account for a majority of patients with early-onset familial AD. However, the clinical indications and algorithms for genetic testing in dementia are still evolving. METHODS: The entire open reading frame of the PS1 gene was sequenced in a series of 414 consecutive patients referred for diagnostic testing, including 372 patients with AD and 42 asymptomatic persons with a strong family history of AD. RESULTS: Forty-eight independent patients screened had a PS1 mutation including 21 novel mutations. In addition, 3% of subjects (11/413) had a known polymorphism, the Glu318Gly substitution. The majority of the mutations were missense substitutions but there were three insertions and Delta exon 10 mutation. With six exceptions (codons 35, 178, 352, 354, 358, and 365) most of the mutations occurred at residues conserved in the homologous PS2 gene or in PS1 of other species. CONCLUSIONS: Eleven percent of a referral-based series of patients with AD can be explained by coding sequence mutations in the PS1 gene. The high frequency of PS1 mutations in this study indicates that screening for PS1 mutations in AD is likely to be successful, especially when directed at patients with a positive family history with onset before 60 years (90% of those with PS1 mutations were affected by age 60 years). This will also have significance for the secondary identification of at-risk relatives who might be candidates for future prophylactic therapies for AD.

Analysis of the c-FOS gene on chromosome 14 and the promoter of the amyloid precursor protein gene in familial Alzheimer's disease.

The c-FOS gene product, a putative transacting transcriptional regulator of the amyloid precursor protein (APP) gene, is a candidate locus for the familial Alzheimer's disease (FAD) mutation on chromosome 14 (FAD14). In light of this functional relationship, we investigated the nucleotide sequence and segregation of c-FOS and the nucleotide sequence of the 5' APP promoter. Single-stranded conformational polymorphisms (SSCPs) in the c-FOS gene revealed that c-FOS closely cosegregates with the FAD14 gene but does not show allelic association with FAD. A conservative third-position T-->C mutation was demonstrated in exon 2 (codon 84) of c-FOS, and a C-->G substitution was detected at -209 bp in the 5' promoter of APP. Neither were unique to FAD and are unlikely to be pathogenic or secondary modifiers of the FAD phenotype. We conclude that the c-FOS open reading frame is probably not the site of the FAD14 locus, but we cannot exclude the existence of modifier loci on chromosome 21.

Failure to detect missense mutations in the S182 gene in a series of late-onset Alzheimer's disease cases.

The possibility of an interaction of multiple genes has been speculated in pathogenesis of Alzheimer's disease (AD). Because we have recently cloned a novel gene S182 bearing five different missense mutations which segregate with early-onset familial AD, we sought the frequency of these mutations in familial and sporadic late-onset AD to clarify the incidence of these mutations in the disease. The current study showed lack of these mutations in 118 independent subjects affected with late-onset Alzheimer's disease.

Interfamilial and intrafamilial phenotypic heterogeneity in familial Alzheimer's disease.

The features of Alzheimer's disease (AD) are very heterogenous, and some component of the variability of AD is likely to be related to genetic factors. To investigate this question, we evaluated 19 clinical neuropsychiatric and brain imaging features in 32 familial Alzheimer's disease (FAD) kindred, primarily of late onset. Within families, patients displayed a high degree of phenotypic heterogeneity (PH), which occurred irrespective of gender, ethnicity, or apolipoprotein E genotype. Overall, an equivalent amount of PH was observed in both the between- (37%) and within-family (31%) groups. However, for onset age and rate of decline between families, there was greater PH than within families (P = .002 and P = .01, respectively). A similar trend was found for severity of cortical atrophy (P = .05). These observations suggest a weak genetic influence, and possibly strong nongenetic influences, on the degree of phenotypic heterogeneity in late-onset FAD. In early-onset AD kindred, a much smaller degree of phenotypic heterogeneity may be expected within families, because genetic influences in phenotypic expression tend to be more prominent in early-onset cases.

[Direct detection of loci with pathologic trinucleotide repeats in diseases with anticipation]. / Priamoe vydelenie lokusov s patologicheski udlinennymi trinukleotidnymi povtorami pri bolezniakh s antitsipatsiei.

We describe a simple method for the identification of pathologically expanded (CCG)n and (CTG)n three nucleotides repeat arrays in the human genome and for the recovery of flanking sequences. We were able to detect the presence of novel high-molecular-weight alleles in at least two of three subjects known to have expanded (CCG)n tracts at the FRAXA locus. The above method may be used for testing of small families or even single affected individuals with disease thought to display clinical evidence of anticipation. The (CCG)n > 200 and (CTG)n > 250 probes may also be useful for individual "DNA fingerprint" identifications.

[Comparison of mitochondrial DNA sequences of T.N. Kulikovskii-Romanov, the nephew of Tsar Nikolai II Romanov, with DNA from the putative remains of the Tsar]. / Sravnenie posledovatel'nostei mitokhondrial'noi DNK T.N. Kulikovskogo-Romanova, plemiannika tsaria Nikolaia II Romanova, plemiannika tsaria Nikolaia II Romanova, i DNK predpolagaemykh ostankov tsaria.

Analysis of two polymorphic regions of mitochondrial DNA obtained from T. N. Kulikovskii-Romanov, the nephew of the last Tsar of the Russian Empire Nikolai II Romanov, was performed. The mitochondrial DNA sequences of T. N. Kulikovskii-Romanov and earlier reported DNA sequences obtained from the putative remains of Nikolai II showed almost complete coincidence except for a single nucleotide at the position 16169. At this position, C was found in mitochondrial DNA of T. N. Kulikovskii-Romanov, C/T in that from the putative remains of Nikolai II Romanov, and T in mitochondrial DNA from great great grandson and great great grand-daughter of Louise Hesse-Cassel. These data suggest independent mutations in the maternal lineage of Louise Hesse-Cassel's descendants and/or a mutation leading to a heteroplasmia in the lineage of Louise Hesse-Cassel.

[Mapping the gene for palmoplantar hyperkeratosis (thylosis) to chromosome 17 in the 17q12-q24 region]. / Kartirovanie gena ladonno-podoshvennogo giperkeratoza (tiloza) na 17-i khromosome v raione 17q12-q24.

Mapping of the genetic defect causing dominant palmoplantaris hyperkeratosis (PPHK) was continued based on the material of an extended Uzbek pedigree. No linkage between the PPHK gene and hypervariable DNA markers from 8p, 12p, 14q, and 22q were revealed. The study of PPHK gene linkage with DNA markers covering the entire length of 17th chromosome mapped the PPHK gene to 17q12-q24 and revealed close linkage with KRT10 and D17S800 loci (zero recombination frequency at a lod score > 7). The possible location of a PPHK mutation in one of the keratin genes mapped to the same region on the 17th chromosome is discussed.

[Obtaining monoclonal antibodies to paired tangled filaments from the brain of patients with Alzheimer's disease]. / Poluchenie monoklonal'nykh antitel k poparno skuchennym filamentam iz mozga bol'nykh bolezn'iu Al'tsgeimera.

Hybridoma technique was used to obtain a clone producing IgG antibodies. Paired helical neurofilaments isolated from the brain of patients suffering from Alzheimer's disease were used as an antigen during preparation of the clone. Antibodies recognize neurons with neurofibrillary changes. Specificity of the obtained antibodies to paired helical filaments was proved immunohistochemically. Monoclonal antibodies obtained are likely to be useful in the determination of the role played by pathological proteins in mutually twisted filaments formation.

[Anti-somatostatin autoantibodies in the blood serum of patients with schizophrenia]. / Uroven' autoantitel k somatostatinu v syvorotke krovi bol'nykh shizofreniei.

Solid-phase IEA was used to measure the level of autoantibodies to somatostatin in the blood serum of 44 schizophrenics and 24 healthy donors. The patients suffering from schizophrenia manifested a higher (p less than 0.01) level of immune responsiveness of the blood serum to somatostatin (0.665 +/- 0.03) as compared to the control group (0.509 +/- 0.05). The main contribution to the differences between the groups as regards the parameter measured is made by patients with malignant (0.810 +/- 0.10) and paranoid (0.773 +/- 0.08) schizophrenia whereas the patients' subgroup with slow-progressive schizophrenia did not differ from normal regarding the level of autoantibodies to somatostatin in the serum (0.504 +/- 0.03). These tentative data agree with a hypothesis of the involvement of autoimmune processes into the development of schizophrenia.

[Is there a relation between the presence in the serum of patients with arterial hypertension of a protein component with molecular weight of 15 kD and the inhibitory effect of the serum on Na,K-ATPase?]. / Sushchestvuet li sviaz' mezhdu prisutstviem v syvorotke krovi bol'nykh arterial'noi gipertenziei belkovogo komponenta s Mr 15 kD i ingibiruiushchim deistviem syvorotki na Na,K-ATFazu?

Blood sera from patients with arterial hypertension exhibited more distinct inhibitory effect on purified Na+,K+-ATPase as compared with blood sera of healthy persons. Moreover, the fraction of 12-15 kDa protein components was usually increased in blood sera of the patients. At the same time, strong inhibition of the enzyme occurred after addition of blood sera which did not contain the protein fraction. The data obtained suggest that both these patterns--the degree of blood sera inhibitory effect on Na+,K+-ATPase activity and content of 12-15 kDa protein components in blood serum--should be considered as diagnostically valuable at early steps of development of hypertension.

[Endogenous Na, K-ATPase inhibitors and biochemical markers of hypertension]. / Endogennye ingibitory Na, K-ATFazy i biokhimicheskie markery gipertonii.

Molecular mechanisms of disturbances in the system responsible for ion transport taking place in the development of the initial hypertension in linear animals have been analysed in this review. On the basis of own and literary data the diagnostic significance of the biochemical parameters which characterize the membrane ion transport state at given disease is estimated. Using the results of correlation analysis of facts which characterize the connection between the human hypertension and specific blood factors, a probability of hypertension development depending on the degree of the given factors expression is determined.

Homozygous inheritance of the Machado-Joseph disease gene.

We report a patient presenting at age 16 years with postural instability and falls who developed severe generalized dystonia by the age of 20 years. He was the product of a consanguineous marriage. Maternal grandfather and paternal grandmother (brother and sister) living in the Azores were both affected by Machado-Joseph disease (MJD) beginning late in life. To date neither of the patient's parents are clinically affected. Linkage studies in this family and others of Azorean descent have confirmed the recent mapping of the MJD gene to chromosome 14q. Genotyping of the members of this pedigree provides strong genetic evidence that our patient is homozygous for the MJD gene. Our results combined with experience in 2 putative homozygotes previously reported in the literature suggest that gene dosage is an important determinant of age of onset and clinical phenotype in MJD. Other possible influencing factors are discussed.

Dopa-responsive parkinsonism phenotype of Machado-Joseph disease: confirmation of 14q CAG expansion.

The subtype IV of Machado-Joseph disease (MJD), characterized by parkinsonism variably combined with ataxia, distal atrophy, and sensory loss, has been all but ignored in recent reports of MJD, including those describing the molecular biologic substrate of the disease. We have demonstrated expansion of the CAG trinucleotide repeat of the MJD1 gene located on chromosome 14q32.1 in 2 patients of Azorean descent who presented with levodopa-responsive atypical parkinsonism. Previous publications have documented the presence of this expanded repeat in the other more common MJD phenotypes (I-III). To our knowledge, this is the first molecular biologic confirmation of the presence of the MJD1 gene in the subtype IV phenotype. Patients presenting with parkinsonism and peripheral neuropathy should be screened for this genetic defect.

The upstream promoter of the beta-amyloid precursor protein gene (APP) shows differential patterns of methylation in human brain.

The human beta-amyloid protein precursor (beta-APP) gene (symbol APP) shows variable levels of expression in different human tissues, including brain. Because at least a moderate level of beta-APP expression is probably a necessary, although not sufficient, condition for diseases associated with pathologic deposition of beta-APP proteolytic products (such as the A beta peptide), we sought to identify factors in the 5' promoter of the human APP gene that may regulate tissue-specific expression of the APP gene. We report that sequences upstream from -500 bp in the APP promoter display complex, tissue-specific patterns of methylation. Furthermore, different patterns of methylation were observed even in DNA from different regions of brain. These differentially methylated sequences are able to bind nuclear proteins expressed in brain and HeLa cells and are also methylated in neocortex of nonhuman primates. Because these methylation patterns crudely reflect differences in APP expression, they may represent one mechanism for the tissue-specific regulation of APP expression.

Are the associations between Alzheimer's disease and polymorphisms in the apolipoprotein E and the apolipoprotein CII genes due to linkage disequilibrium?

Allele frequencies for polymorphisms in the apolipoprotein E and the apolipoprotein CII genes were determined in subjects of Ashkenazi Jewish origin with late-onset Alzheimer's disease and in unaffected control subjects from the same ethnic group. A significant association was observed between late-onset Alzheimer's disease and the epsilon 4 (112Cys-->Arg) allele of apolipoprotein E; however, no association was detected with apolipoprotein CII. These results suggest that the association with epsilon 4 is probably not due to linkage disequilibrium.

A biochemical approach to essential hypertension.

Using multivariate statistical analysis, an attempt has been made to select hypertensive and normotensive sub-groups of subjects on the basis of certain parameters of their blood serum, such as the inhibition of purified Na,K-ATPase by serum and the content of two proteins with molecular masses of 12 and 15 kDa. An analysis of 20 human beings (10 hypertensive and 10 normotensive individuals) revealed that the best division into sub-groups is achieved only through the use of a combination of these three parameters.

Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene.

We report the cloning of a novel gene (E5-1) encoded on chromosome 1 which has substantial nucleotide and amino-acid sequence similarity to the S182 gene on chromosome 14q24.3. Mutations, including three new missense mutations in the S182 gene, are associated with the AD3 subtype of early-onset familial Alzheimer's disease (AD). Both the E5-1 and the S182 proteins are predicted to be integral membrane proteins with seven membrane-spanning domains, and a large exposed loop between the sixth and seventh transmembrane domains. Analysis of the nucleotide sequence of the open reading frame (ORF) of the E5-1 gene led to the discovery of two missense substitutions at conserved amino-acid residues in affected members of pedigrees with a form of familial AD that has a later age of onset than the AD3 subtype (50-70 years versus 30-60 years for AD3). These observations imply that the E5-1 gene on chromosome 1 and the S182 gene on chromosome 14q24.3 are members of a family of genes (presenilins) with related functions, and indicates that mutations in conserved residues of E5-1 could also play a role in the genesis of AD. Our results also indicate that still other AD susceptibility genes exist.