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PubMed2005

Sudden cardiac death and inherited arrhythmia syndromes.

Sudden cardiac death (SCD) at youth is rare and is often caused by inherited cardiac disorders. This review focuses on the genetic background of inherited primary electrical diseases, the so-called "channelopathies." Following a short clinical description of each syndrome, the recent findings in the genetics of long QT syndrome, short QT syndrome, isolated cardiac conduction defect, familial sick sinus syndrome, familial atrial fibrillation, cathecholaminergic polymorphic ventricular tachycardia, familial Wolff-Parkinson-White (WPW) syndrome, and Brugada syndrome are discussed. The currently proposed theoretical model of overlapping phenotypes in SCN5A sodium channel mutations is presented. The recent data indicate that advances in molecular genetics, experimental and clinical electrophysiology shed some light on the genetic background of primary electrical diseases. However, it is also becoming clear that the process from a mutation of a gene to the clinical presentation of a patient is currently only partially understood and extremely complex.

Arrhythmias, Cardiac↗
PubMed2005

Myelin-associated glycoprotein is altered in a familial late-onset orthochromatic leukodystrophy.

Adult-onset dominant leukodystrophies are a heterogeneous group of rare disorders, whose etiology, pathogenesis and molecular background are still unknown. We report the neuropathological and biochemical investigations of the brains and their myelin proteins components in 2 members of an Italian family affected by an adult-onset autosomal dominant leukoencephalopathy. Clinical signs included spastic paraparesis, pseudobulbar syndrome, action tremor of head and hands, and moderate memory impairment. No mental deterioration or neuropathy was present. Onset was subacute (range 42-53 years) and progression spanned 4 to 7 years. The neuropathological phenotype overlapped that of orthochromatic leukodystrophies. The biochemical analysis revealed an abnormal myelin-associated glycoprotein (MAG); the defect was localized at the C-terminal domain of the L-MAG isoform, resulting in a protein approximately 5 kDa shorter than the normal counterpart. No mutation in the MAG gene-coding regions was uncovered, and linkage analysis formally excluded the entire MAG locus. We show that the identified MAG protein alteration is probably due to an abnormal post-translational event. Considering MAG function in the maintenance of myelin, the abnormal protein may have a role in the pathogenesis of this disease. This is the first report of a possible pathogenetic role of MAG in a hereditary disease affecting the central white matter.

Adult↗
PubMed2004

Expression of acrB, acrF, acrD, marA, and soxS in Salmonella enterica serovar Typhimurium: role in multiple antibiotic resistance.

Comparative reverse transcription-PCR in combination with denaturing high-pressure liquid chromatography analysis was used to determine the levels of expression of soxS, marA, acrF, acrB, and acrD in multiple-antibiotic-resistant (MAR) Salmonella enterica serovar Typhimurium isolates and mutants of S. enterica serovar Typhimurium SL1344 with defined deletions. Posttherapy MAR clinical isolates had increased levels of expression of all genes except soxS. S. enterica serovar Typhimurium SL1344 Delta acrB expressed 7.9-fold more acrF than the parent strain. A strain with an acrF deletion expressed 4.6-fold more acrB. Deletion of acrB and/or acrF resulted in 2.7- to 4.3-fold more marA mRNA and 3.6- to 4.9-fold increases in the levels of expression of acrD but had a variable effect on the expression of soxS. All mutants were hypersusceptible to antibiotics, dyes, and detergents; but the MIC changes were more noticeable for SL1344 with the acrB deletion than for the mutant with the acrF disruption. These mutants had different but overlapping phenotypes, and the concentrations of ciprofloxacin accumulated by the mutants were different. These data suggest that acrB, acrF, and acrD are coordinately regulated and that their expression influences the expression of the transcriptional activators marA and soxS.

Anti-Infective Agents↗
PubMed2000

Meiotic segregation, synapsis, and recombination checkpoint functions require physical interaction between the chromosomal proteins Red1p and Hop1p.

In yeast, HOP1 and RED1 are required during meiosis for proper chromosome segregation and the consequent formation of viable spores. Mutations in either HOP1 or RED1 create unique as well as overlapping phenotypes, indicating that the two proteins act alone as well as in concert with each other. To understand which meiotic processes specifically require Red1p-Hop1p hetero-oligomers, a novel genetic screen was used to identify a single-point mutation of RED1, red1-K348E, that separates Hop1p binding from Red1p homo-oligomerization. The Red1-K348E protein is stable, phosphorylated in a manner equivalent to Red1p, and undergoes efficient homo-oligomerization; however, its ability to interact with Hop1p both by two-hybrid and coimmunoprecipitation assays is greatly reduced. Overexpression of HOP1 specifically suppresses red1-K348E, supporting the idea that the only defect in the protein is a reduced affinity for Hop1p. red1-K348E mutants exhibit reduced levels of crossing over and spore viability and fail to undergo chromosome synapsis, thereby implicating a role for Red1p-Hop1p hetero-oligomers in these processes. Furthermore, red1-K348E suppresses the sae2/com1 defects in meiotic progression and sporulation, indicating a previously unknown role for HOP1 in the meiotic recombination checkpoint.

Alleles↗
PubMed2005

A filamin A splice mutation resulting in a syndrome of facial dysmorphism, periventricular nodular heterotopia, and severe constipation reminiscent of cerebro-fronto-facial syndrome.

BACKGROUND: Mutations of the filamin A locus (FLNA) on Xq28 have been established in girls with periventricular nodular heterotopia and in patients with otopalatodigital and overlapping phenotypes, the pathogenesis of these phenotypes being thought to be quite distinct. To date only six male cases of periventricular nodular heterotopia (PVNH) have been reported and these almost invariably associated with severe neurological signs. METHODS AND RESULTS: We report a new phenotype of male PVNH, with relatively normal development, no epilepsy or other neurological abnormality, severe constipation, and facial dysmorphism and without a discernible skeletal phenotype. This phenotype is associated with a splice site mutation in FLNA c.1923C>T, resulting in the generation of both normal and aberrant mRNA. CONCLUSIONS: We postulate that the patient retains enough FLNA function to avoid the usual lethality associated with loss of function mutations in males and suggest that the severe constipation may be a clue to the molecular aetiology of other X linked conditions associated with severe constipation.

Abnormalities, Multiple↗
PubMed1989

Early onset Cockayne's syndrome: case reports with neuropathological and fibroblast studies.

Two patients with early onset Cockayne's syndrome are presented. In each case there was a striking failure of growth and developmental deterioration around six months of age. It has been suggested that early onset Cockayne's syndrome is a syndrome distinct from Cockayne's syndrome, but when the first patient died aged two years 10 months, examination of the brain showed a leucodystrohy with 'tigroid' demyelination similar to that reported in later onset cases of Cockayne's syndrome. Studies of the effects of UV irradiation on cultured fibroblasts from patients showed similar levels of inhibition of RNA synthesis to those seen in a control with Cockayne's syndrome. This evidence suggests it is appropriate to classify early onset Cockayne's syndrome with Cockayne's syndrome. Since there is a phenotypic overlap between early onset Cockayne's syndrome and COFS syndrome, they may both be classified within the same diagnostic group, but as yet no cellular studies with UV irradiation have been performed in COFS syndrome.

Brain↗
PubMed1996

Two sibs with Wolf-Hirschhorn and DiGeorge deletions resulting from an unbalanced chromosome rearrangement, 45,XX/XY, der(4)t(4;22) (p16.3;q11.2) mat,-22.

A mother with apparently balanced translocation between chromosomes 4 and 22 gave birth to two children (sib 1 and twin A) with 45,XX,der(4)t(4;22) (p16.3;q11.2)mat,-22 and 45,XY,der(4)t(4; 22(p16.3;q11.2)mat,-22 karyotypes. The mother was a slow learner and required special education. The imbalance in the sibs arose through a 3:1 malsegregation in the mother. The net result was deletions 4p16.3pter and 22q11.2pter. Deletion 4p is associated with Wolf-Hirschhorn syndrome (WHS). The 22q11.2 microdeletion is associated with a wide range of overlapping phenotypes including DiGeorge syndrome (DGS), velocardiofacial syndrome (VCFS), conotruncal facial abnormality, and sporadic or familial cardiac defect. Fluorescence in situ hybridisation (FISH) was performed. Cosmid probes D4S96, which maps to 4p16.3, and D22S75, which maps to 22q11.2, were used. In the mother, the translocation breakpoints were proximal to D4S96 on chromosome 4 and distal D22S75 on chromosome 22. The two sibs had deletions of a D4S96 and a D22S75 probe loci. Sib 1, a 2 1/2 year old girl, has multiple congenital abnormalities and profound developmental delay. The craniofacial features were generally of WHS. Hypoplasia of the thymus hypocalcaemia, and seizures in early infancy, which are clinical features of DGS, were also observed. Twin A was one of a pair of dizygotic twins. He had multiple congenital abnormalities and died soon after birth.

Abnormalities, Multiple↗
PubMed1998

Atelosteogenesis type 2.

Atelosteogenesis type 2 (AO2) (MIM 256050) is a neonatally lethal chondrodysplasia characterised by severe limb shortening and deficient ossification of parts of the skeleton. Other features include facial dysmorphism, cleft palate, talipes, and abducted thumbs and toes. Phenotypic overlap with non-lethal diastrophic dysplasia (DTD) suggested a common aetiology and it has recently been confirmed that both syndromes result from mutations in the DTDST (diastrophic dysplasia sulphate transporter) gene.

Abnormalities, Multiple↗
PubMed1998

Two 22q telomere deletions serendipitously detected by FISH.

Cryptic telomere deletions have been proposed to be a significant cause of idiopathic mental retardation. We present two unrelated subjects, with normal G banding analysis, in whom 22q telomere deletions were serendipitously detected at two different institutions using fluorescence in situ hybridisation (FISH). Both probands presented with several of the previously described features associated with 22q deletions, including hypotonia, developmental delay, and absence of speech. Our two cases increase the total number of reported 22q telomere deletions to 19, the majority of which were identified by cytogenetic banding analysis. With the limited sensitivity of routine cytogenetic studies (approximately 2-5 Mb), these two new cases suggest that the actual prevalence of 22q telomere deletions may be higher than currently documented. Of additional interest is the phenotypic overlap with Angelman syndrome (AS) as it raises the possibility of a 22q deletion in patients in whom AS has been ruled out. The use of telomeric probes as diagnostic reagents would be useful in determining an accurate prevalence of chromosome 22q deletions and could result in a significantly higher detection rate of subtelomeric rearrangements.

Child, Preschool↗
PubMed2003

Biochemical and genetic association of plasma apolipoprotein A-II levels with familial combined hyperlipidemia.

Apolipoprotein A-II (apoA-II) is a major protein on high-density lipoprotein (HDL) particles, and in mice, its levels are associated with triglyceride and glucose metabolism. In particular, transgenic mice overexpressing apoA-II exhibit hypertriglyceridemia, increased body fat, and insulin resistance, whereas apoA-II-null mice have decreased triglycerides and increased insulin sensitivity. Given the phenotypic overlap between familial combined hyperlipidemia (FCH) and apoA-II transgenic mice, we investigated the relationship of apoA-II to this disorder. Despite having lower HDL-cholesterol (HDL-C), FCH subjects had higher apoA-II levels compared with unaffected relatives (P<0.00016). Triglyceride and HDL-C levels were significant predictors of apoA-II, demonstrating that apoA-II variation is associated with several FCH-related traits. After adjustment for multiple covariates, there was evidence for the heritability of apoA-II levels (h2=0.15; P<0.02) in this sample. A genome scan for apoA-II levels identified significant evidence (LOD=3.1) for linkage to a locus on chromosome 1q41, coincident with a suggestive linkage for triglycerides (LOD score=1.4). Thus, this locus may have pleiotropic effects on apoA-II and FCH traits. Our results demonstrate that apoA-II is biochemically and genetically associated with FCH and may serve as a useful marker for understanding the mechanism by which FCH develops.

Adult↗
PubMed2003

Suggestive linkage to chromosomal regions 13q31 and 22q12 in families with psychotic bipolar disorder.

OBJECTIVE: Linkage studies of bipolar disorder and schizophrenia have found overlapping evidence for susceptibility genes in four chromosomal regions-10p12-14, 13q32, 18p11.2, and 22q12-13. The authors previously demonstrated familial clustering of psychotic symptoms-defined as hallucinations and/or delusions-in some bipolar disorder pedigrees. In this study they used stratified linkage analysis to test the hypothesis that those bipolar disorder pedigrees most enriched for psychotic symptoms would show greater evidence of linkage to the regions of previous bipolar disorder/schizophrenia linkage overlap. METHOD: Nonparametric linkage analyses using GENEHUNTER and ASPEX were performed on 65 bipolar disorder families. Family subsets were defined by the number of family members with psychotic mood disorder. RESULTS: The 10 families in which three or more members had psychotic mood disorder showed suggestive evidence of linkage to 13q31 (nonparametric linkage score=3.56; LOD score=2.52) and 22q12 (nonparametric linkage score=3.32; LOD score=3.06). These results differed significantly from those for the entire study group of 65 families, which showed little or no linkage evidence in the two regions. The 10 families with three or more psychotic members did not show evidence of linkage to 10p12-14 or 18p11.2. The 95% confidence interval on 22q12 spanned 4.3 centimorgans (2.6 megabases) and was congruent with previous findings. CONCLUSIONS: Bipolar disorder families in which psychotic symptoms cluster may carry susceptibility genes on chromosomal regions 13q31 and 22q12. Replication should be attempted in similar families and perhaps in schizophrenia families in which mood symptoms cluster because these overlapping phenotypes may correlate most closely with the putative susceptibility genes. The localization of the 22q12 finding particularly encourages further study of this region.

Affective Disorders, Psychotic↗
PubMed1997

Ectopic expression of SPARC in Xenopus embryos interferes with tissue morphogenesis: identification of a bioactive sequence in the C-terminal EF hand.

SPARC is a matricellular Ca(2+)-binding glycoprotein that exhibits both counteradhesive and antiproliferative effects on cultured cells. It is secreted by cells of various tissues as a consequence of morphogenesis, response to injury, and cyclic renewal and/or repair. In an earlier study with Xenopus embryos we had shown a highly specific and regulated pattern of SPARC expression. We now show that ectopic expression of SPARC before its normal embryonic activation produces severe anomalies, some of which are consistent with the functions of SPARC proposed from studies in vitro. Microinjection of SPARC RNA, protein, and peptides into Xenopus embryos before endogenous embryonic expression generated different but overlapping phenotypes. (a) Injection of SPARC RNA into one cell of a two-cell embryo resulted in a range of unilateral defects. (b) Precocious exposure of embryos to SPARC by microinjection of protein into the blastocoel cavity was associated with certain axial defects comparable to those obtained with SPARC RNA. (c) SPARC peptides containing follistatin-like and copper-binding sequences were without obvious effect, whereas SPARC peptide 4.2, corresponding to a disulfide-bonded, Ca(2+)-binding domain, was associated with a reduction in axial structures that led eventually to complete ventralization of the embryos. Histological analysis of ventralized embryos indicated that the morphogenetic events associated with gastrulation might have been inhibited. Microinjection of other Ca(2+)-binding glycoproteins, such as osteopontin and bone sialoprotein, resulted in phenotypes that were unique. We probed further the structural correlates of this region of SPARC in the context of tissue development. Co-injection of peptide 4.2 with Ca2+ or EGTA, and injection of peptide 4.2K (containing a mutated consensus Ca(2+)-binding sequence), demonstrated that the developmental defects associated with peptide 4.2 were independent of Ca2+. However, the disulfide bridge in this region of SPARC was found to be critical, as injection of peptide 4.2AA, a mutant lacking the cystine, generated no axial defects. We have therefore shown for the first time in vivo that the temporally inappropriate presence of SPARC is associated with perturbations in tissue morphogenesis. Moreover, we have identified at least one bioactive region of SPARC as the C-terminal disulfide-bonded, Ca(2+)-binding loop that was previously shown to be both counteradhesive and growth-inhibitory.

Amino Acid Sequence↗
PubMed2001

Neuropathology of occipital horn syndrome.

Occipital horn syndrome, formerly known as Ehlers-Danlos syndrome type IX or X-linked cutis laxa, is an allelic variant of Menkes' syndrome. Although the clinical symptomatology and systemic pathology findings have been well described in occipital horn syndrome, the neuropathology has not previously been reported. A kindred affected by the X-linked occipital horn syndrome is followed at the University of Alabama at Birmingham. A severely mentally retarded dysmorphic man, who died at the age of 26 years, never gained the ability to walk or talk. Among other findings at autopsy, the patient had the skeletal anomalies previously described with occipital horn syndrome. Neuropathologic findings included neovascularization and extreme reduplication of the cerebral arteries, in conjunction with cystic medial degeneration; bilateral cerebellar hypoplasia; focal cortical dysplasia, and cerebellar heterotopias. These findings are similar to those seen in the brains of patients with Menkes' syndrome, which is not surprising, given the known phenotypic overlap and the proven allelism of occipital horn syndrome with classic Menkes' syndrome.

Adolescent↗
PubMed1992

Epidermal nevus syndrome: subgroup with neuronal migration defects.

Epidermal nevus syndrome is one of the sporadic congenital hamartoses in which neurologic abnormalities have been frequently reported. We report two cases with severe primary brain involvement, seizures, mental retardation, and facial hemihypertrophy. We emphasize the superiority of magnetic resonance imaging over other radiographic studies in outlining the primary central nervous system anomalies associated with this syndrome. Although attempts were made to distinguish between several variants of epidermal nevus syndrome, it is clear that these are one entity. Proteus syndrome, encephalocraniocutaneous lipomatosis, and epidermal nevus syndrome have several overlapping phenotypic features. We suggest that they represent a phenotypic continuum, which in turn suggests a common pathogenetic process. While the cause of these syndromes is unknown, observations point to a somatic mutation leading to variable patterns of mosaicism.

Abnormalities, Multiple↗
PubMed2026

Achromobacter species in cystic fibrosis and chronic lung disease: a review of virulence, antibiotic resistance, diagnostic challenges, and emerging therapies.

Achromobacter species (spp) is an emerging opportunistic organism more frequently isolated from immunocompromised patients' and hospital settings. This bacterium was once considered an environmental bacterium, but now it is recognized as a serious cause of respiratory infections, bloodstream infections, and urinary tract infections, particularly among patients with cystic fibrosis (CF), chronic illnesses, and medical devices. The purpose of this review is to highlight Achromobacte's clinical significance, pathogenic mechanism, and recent approaches for diagnosis and treatment. By utilizing specific keywords relevant to Achromobacter spp., a comprehensive literature search was performed in PubMed and Google Scholar. To summarize existing knowledge and highlight gaps in the literature, peer-reviewed studies on clinical relevance, pathogenicity, antimicrobial resistance, and therapeutic approaches were gathered, screened, and narratively assembled. Among the 19 identified species, Achromobacter xylosoxidans (A. xylosoxidans) is the most prevalent and clinically relevant, especially in CF settings. This review explores the organism's microbiological characteristics, virulence strategies-including robust biofilm formation, motility, and secretion systems-and its alarming intrinsic and acquired resistance to antibiotics. Misidentification due to phenotypic overlap with other non-fermenting Gram-negative bacilli complicates diagnosis, while limited MALDI-TOF MS and database representation hinders species-level identification. Genotyping methods, including multi-locus sequence analysis and housekeeping gene sequencing, offer superior resolution but remain underutilized in clinical diagnostics. With rising resistance mediated by &#x3b2;-lactamases, efflux pumps, and adaptive genomic traits, Achromobacter spp presents a growing challenge for treatment and infection control. This review highlights the urgent need for improved diagnostic strategies, species-level clinical and microbiological data, and tailored therapeutic approaches to manage Achromobacter spp. infections effectively.

Humans↗
PubMed2006

Differential expression of a new isoform of DLG2 in renal oncocytoma.

BACKGROUND: Renal oncocytoma, a benign tumour of the kidney, may pose a differential diagnostic problem due to overlapping phenotype with chromophobe renal cell carcinoma or other types of renal cell tumours. Therefore, identification of molecular markers would be of great value for molecular diagnostics of this tumour type. METHODS: In the current study we applied various techniques, including Affymetrix microarray hybridization and semiquantitative RT-PCR, to identify genes expressed differentially in renal oncocytomas. Subsequently, we used RACE and Northern blot hybridization to characterize the potential candidates for molecular diagnosis. RESULTS: We have identified new isoform of DLG2 gene, which contains 3'-end exons of the known DLG2 gene along with the hypothetical gene FLJ37266. The new isoform is specifically upregulated in renal oncocytoma, whereas the known DLG2 gene is downregulated in this type of kidney tumour. CONCLUSION: The new isoform of DLG2 is the promising candidate gene for molecular differential diagnostics of renal oncocytoma.

Adenoma, Oxyphilic↗
PubMed2024

ASXL1 truncating variants in BOS and myeloid leukemia drive shared disruption of Wnt-signaling pathways but have differential isoform usage of RUNX3.

BACKGROUND: Rare variants in epigenes (a.k.a. chromatin modifiers), a class of genes that control epigenetic regulation, are commonly identified in both pediatric neurodevelopmental syndromes and as somatic variants in cancer. However, little is known about the extent of the shared disruption of signaling pathways by the same epigene across different diseases. To address this, we study an epigene, Additional Sex Combs-like 1 (ASXL1), where truncating heterozygous variants cause Bohring-Opitz syndrome (BOS, OMIM #605039), a germline neurodevelopmental disorder, while somatic variants are driver events in acute myeloid leukemia (AML). No BOS patients have been reported to have AML. METHODS: This study explores common pathways dysregulated by ASXL1 variants in patients with BOS and AML. We analyzed whole blood transcriptomic and DNA methylation data from patients with BOS and AML with ASXL1-variant (AML-ASXL1) and examined differential exon usage and cell proportions. RESULTS: Our analyses identified common molecular signatures between BOS and AML-ASXL1 and highlighted key biomarkers, including VANGL2, GRIK5 and GREM2, that are dysregulated across samples with ASXL1 variants, regardless of disease type. Notably, our data revealed significant de-repression of posterior homeobox A (HOXA) genes and upregulation of Wnt-signaling and hematopoietic regulator HOXB4. While we discovered many shared epigenetic and transcriptomic features, we also identified differential splice isoforms in RUNX3 where the long isoform, p46, is preferentially expressed in BOS, while the shorter p44 isoform is expressed in AML-ASXL1. CONCLUSION: Our findings highlight the strong effects of ASXL1 variants that supersede cell-type and even disease states. This is the first direct comparison of transcriptomic and methylation profiles driven by pathogenic variants in a chromatin modifier gene in distinct diseases. Similar to RASopathies, in which pathogenic variants in many genes lead to overlapping phenotypes that can be treated by inhibiting a common pathway, our data identifies common pathways for ASXL1 variants that can be targeted for both disease states. Comparative approaches of high-penetrance genetic variants across cell types and disease states can identify targetable pathways to treat multiple diseases. Finally, our work highlights the connections of epigenes, such as ASXL1, to an underlying stem-cell state in both early development and in malignancy.

Humans↗
PubMed1999

Concurrence of Pendred syndrome, autoimmune thyroiditis, and simple goiter in one family.

Pendred syndrome is the autosomal recessively transmitted association of familial goiter and congenital deafness. There is no specific biochemical marker of this disease, and the diagnosis depends upon the demonstration of the triad of congenital sensorineural hearing loss, goiter, and abnormal perchlorate discharge test. Pendred syndrome is caused by mutations within the putative ion transporter gene (PDS gene), located on chromosome 7q. A wide variation in the clinical presentation of this condition, and its well documented phenotypic overlap with other thyroid disorders (such as Hashimoto's thyroiditis), can lead to diagnostic difficulties. The potential for misdiagnosis increases when these disorders occur coincidentally in the same family. We describe a kindred in which Pendred syndrome, autoimmune thyroiditis, and simple goiter coexisted, to highlight these diagnostic pitfalls and to illustrate the use of mutational analysis in resolving diagnostic confusion.

Adult↗