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At least 1,405 records · Page 78Linked to original sources
PubMed1999

Genetic, cytogenetic and physical refinement of the autosomal recessive CMT linked to 5q31-q33: exclusion of candidate genes including EGR1.

Charcot-Marie-Tooth disease is an heterogeneous group of inherited peripheral motor and sensory neuropathies with several modes of inheritance: autosomal dominant, X-linked and autosomal recessive. By homozygosity mapping, we have identified, in the 5q23-q33 region, a third locus responsible for an autosomal recessive form of demyelinating CMT. Haplotype reconstruction and determination of the minimal region of homozygosity restricted the candidate region to a 4 cM interval. A physical map of the candidate region was established by screening YACs for microsatellites used for genetic analysis. Combined genetic, cytogenetic and physical mapping restricted the locus to a less than 2 Mb interval on chromosome 5q32. Seventeen consanguineous families with demyelinating ARCMT of various origins were screened for linkage to 5q31-q33. Three of these seventeen families are probably linked to this locus, indicating that the 5q locus accounts for about 20% of demyelinating ARCMT. Several candidate genes in the region were excluded by their position on the contig and/or by sequence analysis. The most obvious candidate gene, EGR1, expressed specifically in Schwann cells, mapped outside of the candidate region and no base changes were detected in two families by sequencing of the entire coding sequence.

Base Sequence↗
PubMed2002

A novel recessive hyperekplexia allele GLRA1 (S231R): genotyping by MALDI-TOF mass spectrometry and functional characterisation as a determinant of cellular glycine receptor trafficking.

Hyperekplexia or startle disease (stiff baby syndrome, STHE) is a hereditary neurological disorder characterised by an exaggerated startle response and infantile muscle hypertonia. Several autosomal dominant and recessive forms of the disorder have been associated with point mutations in GLRA1, the human gene encoding the alpha 1 subunit of the inhibitory glycine receptor. Here, we describe a recessive point mutation (C1073G) in exon 7 of GLRA1 leading to an amino acid exchange of serine 231 to arginine in transmembrane region TM1. The mutation was detectable by restriction digest analysis of genomic PCR amplimers by matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF-MS). Genotyping of family members was performed using an allele specific primer extension assay in combination with MALDI-TOF-MS and confirmed by conventional DNA sequencing. These studies demonstrate the broad applicability of MALDI-TOF-MS as a comparative screening tool applicable to the analysis of allelic gene variants. In comparison to the wild type alpha 1 subunit, biochemical, electrophysiological, and confocal microscopy data indicate a reduced integration of functional alpha 1(S231R) glycine receptors into the cell surface membrane upon recombinant expression. Apparently, the amino acid exchange S231R influences glycine receptor biogenesis and cellular trafficking by introducing a positive charge into transmembrane region TM1.

Base Sequence↗
PubMed2004

Microarray-based mutation analysis of the ABCA4 (ABCR) gene in autosomal recessive cone-rod dystrophy and retinitis pigmentosa.

Mutations in the ABCA4 gene have been associated with autosomal recessive Stargardt disease (STGD1), cone-rod dystrophy (CRD), and retinitis pigmentosa (RP). We employed a recently developed genotyping microarray, the ABCR400-chip, to search for known ABCA4 mutations in patients with isolated or autosomal recessive CRD (54 cases) or RP (90 cases). We performed detailed ophthalmologic examinations and identified at least one ABCA4 mutation in 18 patients (33%) with CRD and in five patients (5.6%) with RP. Single-strand conformation polymorphism (SSCP) analysis and subsequent DNA sequencing revealed four novel missense mutations (R24C, E161K, P597S, G618E) and a novel 1-bp deletion (5888delG). Ophthalmoscopic abnormalities in CRD patients ranged from minor granular pigmentary changes in the posterior pole to widespread atrophy. In 12 patients with recordable electroretinogram (ERG) tracings, a cone-rod pattern was detected. Three patients demonstrated progression from a retinal dystrophy resembling STGD1 to a more widespread degeneration, and were subsequently diagnosed as CRD. In addition to a variable degree of atrophy, all RP patients displayed ophthalmologic characteristics of classic RP. When detectable, ERG recordings in these patients demonstrated rod-cone patterns of photoreceptor degeneration. In conclusion, in this study, we show that the ABCA4 mutation chip is an efficient first screening tool for arCRD.

ATP-Binding Cassette Transporters↗
PubMed2005

Unilateral recession-resection in children with exotropia of the convergence insufficiency type.

PURPOSE: The surgical success rates for intermittent exotropia of the convergence insufficiency type have been reported to be variable, and most were studied retrospectively in adults. The purpose of this study was to evaluate prospectively the long-term surgical results of unilateral lateral rectus (LR) muscle recession and medial rectus (MR) muscle resection in children with intermittent exotropia of the convergence insufficiency type. METHODS: A total of 14 children with intermittent exotropia greater at near than at distance by 10 prism diopters (PD) or more were included in this prospective study. The amounts of resection and recession were based on near and distance deviation, respectively. Minimum follow-up was 1 year (mean 26.6 months; range, 12-68 months) after surgery. The paired t-test was used to compare preoperative and postoperative measurements of the angle of deviation at distance and near, near-distance difference. RESULTS: Significant postoperative reduction was achieved in terms of mean distance exodeviation, from 22.5 PD to 9.1 PD (P=0.000), and mean near exodeviation from 33.8 PD to 13.6 PD (P=0.000). Mean near-distance difference reduced from 11.3 PD preoperatively to 4.6 PD postoperatively (P=0.000). Fresnel prism was used temporarily to treat postoperative esotropia in only one patient for postoperative 6 months. CONCLUSIONS: Unilateral surgery biased to MR strengthening more than LR weakening in children with intermittent exotropia of the convergence insufficiency type, was found to successfully reduce both distance and near deviation and to collapse near-distance differences with a low risk of long-term postoperative esotropia.

Child↗
PubMed2005

Individually addressable recessed gold microelectrode arrays with monolayers of thio-cyclodextrin nanocavities.

Four, individually addressable 30 microm diameter, e-beam deposited, gold microelectrodes recessed by 6 microm were suitably spaced on a single substrate to avoid diffusional overlap between each microelectrode. The single substrate device was functionalised with thiolated alpha-, beta-, and gamma-cyclodextrin nanocavities without spacer groups to ensure close proximity of the cavities to the electrode surface. The microelectrodes were assessed in two stages. The e-beam deposited micron sized electrodes were characterized using models for recessed and inlaid microdisk electrodes. Subsequently, each individually addressable, atomically flat, micro-patterned gold electrode with thiolated CD ensembles was treated as a nanoporous electrode assembly. Theoretical and experimental results were compared using cyclic voltammetry. Atomic force microscopy was also used to characterise the modified microelectrodes. Comparisons were made with thiolated CDs deposited on macroelectrodes. This is the first report of the behaviour of immobilized CD nanocavities ensembles on atomically flat gold microelectrodes.

Journal Article↗
PubMed1997

Frequent de novo mutations of the ANK1 gene mimic a recessive mode of transmission in hereditary spherocytosis: three new ANK1 variants: ankyrins Bari, Napoli II and Anzio.

A subset of spherocytosis cases associated with mutations of the ANK1 gene present an apparently recessive inheritance pattern on a clinical and haematological basis. We identified three novel out-of-frame deletions in the ANK1 gene: allele Bari (1361delG), Napoli II (2883delC) and Anzio (3032delCA) in three Italian patients, two of whom have been splenectomized. Analysis of the cDNA showed small or trace amounts of ankyrin mRNAs in Bari, Napoli II and Anzio. The parents were normal clinically and haematologically and did not carry the mutations exhibited by their children. We confirmed the de novo character of the HS mutations based on paternity testing. Recessive HS associated with the ANK1 gene is probably rarer than initially thought, and spherocytosis may often be due to de novo mutations.

Ankyrins↗
PubMed1999

A recurrent COL7A1 mutation, R2814X, in British patients with recessive dystrophic epidermolysis bullosa.

Mutations in the type VII collagen gene, COL7A1, underlie all forms of dystrophic epidermolysis bullosa (DEB). The identification of COL7A1 mutations in DEB is complicated because the COL7A1 gene contains 118 distinct exons and most mutations are specific to individual families. In an attempt to simplify mutation screening procedures we searched for recurrent mutations in genomic DNA from 38 British patients with recessive DEB using polymerase chain reaction (PCR), heteroduplex analysis and direct nucleotide sequencing. We identified a recurrent premature termination codon, R2814X, on three out of 76 alleles. Previously we identified the COL7A1 mutations R578X and 7786delG as other frequent molecular abnormalities in British recessive DEB patients. Taken together, these three mutations account for approximately 25% of the molecular pathology of this disease in our population discovered thus far and we recommend initial screening for these mutations by PCR and restriction analysis before undertaking more exhaustive COL7A1 gene analysis. Such an approach is likely to reveal underlying COL7A1 mutations in a significant number of cases.

Collagen↗
PubMed2001

Autopsy case of autosomal recessive hereditary spastic paraplegia with reference to the muscular pathology.

An autopsied case of autosomal recessive hereditary spastic paraplegia with severe neurogenic muscular atrophy is described herein. This patient, a 16-year-old woman, presented with gait disturbance. She developed progressive spastic paralysis of the upper and lower limbs and mental deterioration. She became bedridden at approximately 40years of age. Dysarthria worsened at 45 years of age. She died of pneumonia at 50 years of age. Her younger sister has shown similar clinical symptoms and became bedridden at 37 years of age. Their parents were second cousins. Autopsy revealed a severely atrophic brain, weighing 720 g. The cerebral cortex was thin, and the white matter was extremely reduced in volume. Microscopically, neuronal loss and variable astrogliosis with diffuse spongy changes were evident at the cerebral cortex, thalamic nuclei, basal ganglia and hippocampus. The remaining neurons were atrophied with heavy deposition of lipofuscin. In the spinal cord, the pyramidal tracts as well as the dorsal spinocerebellar tracts were degenerated. In addition, marked loss of the anterior horn cells was seen. Severe neuronal loss of the nucleus gracilis was also detected. In contrast, only mild degeneration of the ventral spinocerebellar tracts and fasciulus cuneatus in the spinal cord were observed. In the frozen sections of skeletal muscle, severe neurogenic atrophy and fatty infiltration were evident. In addition, several rimmed vacuoles were observed in the atrophic fibers, and cytochrome coxidase-deficient fibers were present in part. Reduced nicotinamide adenine dinucleotide (NADH)-tetrazolium reductase reaction revealed abnormal accumulation of mitochondria around the center of the non-atrophic muscle fibers. It is suggested that an analysis of mitochondrial function of Japanese autosomal recessive hereditary spastic hemiplegia may provide additional information to clarify the pathogenesis.

ATPases Associated with Diverse Cellular Activitie↗
PubMed1998

A model of autosomal recessive Alport syndrome in English cocker spaniel dogs.

BACKGROUND: Dogs with naturally occurring genetic disorders of basement membrane (type IV) collagen may serve as animal models of Alport syndrome. METHODS: An autosomal recessive form of progressive hereditary nephritis (HN) was studied in 10 affected, 3 obligate carrier, and 4 unaffected English cocker spaniel (ECS) dogs. Clinical, pathological, and ultrastructural features of the disease were characterized. Expression of basement membrane (BM) proteins was examined with an immunohistochemical technique using monospecific antibodies. RESULTS: Affected dogs had proteinuria and juvenile-onset chronic renal failure. Glomerular basement membrane (GBM) thickening and multilamellation typical of HN were observed in all renal specimens obtained from proteinuric dogs, and severity of GBM ultrastructural abnormalities varied with the clinical stage of disease. Expression of alpha3(IV) and alpha4(IV) chains was totally absent in the kidney of affected dogs. Expression of alpha5(IV) and a6(IV) chains was normal in Bowman's capsule, collecting tubular BM and epidermal BM of affected dogs. The alpha5(IV) chain was not expressed in distal tubular BM of affected dogs. Expression of alpha5(IV) chains was markedly reduced but not absent, and expression of alpha6(IV) chains was present in GBM of affected dogs. Expression of alpha1-alpha2(IV) chains in GBM of affected dogs was increased. Features of obligate carriers were similar to those of unaffected dogs. CONCLUSIONS: We conclude that HN in ECS dogs is a naturally occurring animal model of autosomal recessive Alport syndrome. However, it differs from human disease in the persistence of alpha5(IV) chains in GBM and in the appearance of a6(IV) chains in GBM.

Animals↗
PubMed2005

Autosomal recessive axonal form of Charcot-Marie-Tooth Disease caused by compound heterozygous 3'-splice site and Ser130Cys mutation in the GDAP1 gene.

A recessive demyelinating subtype of Charcot-Marie-Tooth disease called CMT4 is a heterogeneous group of disorders. A relatively frequent form of recessive CMT (CMT4 A) has been mapped to the chromosome 8 q21 and shown to be caused by mutations in the ganglioside-induced differentiation protein 1 (GDAP1) gene. Twenty mutations in the GDAP1 gene have been reported in patients suffering from the axonal and demyelinating forms of CMT disease. In this study we report two novel mutations in the GDAP1 gene in a patient suffering from CMT2 disease and whose parents were asymptomatic carriers of a Ser130Cys and 3'-splice site (311-1G > A) mutation, respectively.

Charcot-Marie-Tooth Disease↗
PubMed1991

[Short- and intermediate-term angular results of Cüppers retro-equatorial myopexy, with or without additional simultaneous recession].

79 variable esotropias underwent bilateral "Fadenoperations". In the first group, the posterior fixation has been performed alone. In the second series, conventional symmetrical recessions of the medial recti have been performed during the same procedure. Two further additional weakening techniques are compared in the last group: anterior medial tenotomies and the so-called "stretch effect". Concomittant recessions considerably enforced the amount of angle reduction for distance and near without affecting precision, predictibility and stability of the results. Tenotomies and stretching procedures were followed by inconstant results.

Accommodation, Ocular↗
PubMed2001

Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM.

CD40 is a member of the tumor necrosis factor receptor superfamily, expressed on a wide range of cell types including B cells, macrophages, and dendritic cells. CD40 is the receptor for CD40 ligand (CD40L), a molecule predominantly expressed by activated CD4(+) T cells. CD40/CD40L interaction induces the formation of memory B lymphocytes and promotes Ig isotype switching, as demonstrated in mice knocked-out for either CD40L or CD40 gene, and in patients with X-linked hyper IgM syndrome, a disease caused by CD40L/TNFSF5 gene mutations. In the present study, we have identified three patients with an autosomal recessive form of hyper IgM who fail to express CD40 on the cell surface. Sequence analysis of CD40 genomic DNA showed that one patient carried a homozygous silent mutation at the fifth base pair position of exon 5, involving an exonic splicing enhancer and leading to exon skipping and premature termination; the other two patients showed a homozygous point mutation in exon 3, resulting in a cysteine to arginine substitution. These findings show that mutations of the CD40 gene cause an autosomal recessive form of hyper IgM, which is immunologically and clinically undistinguishable from the X-linked form.

CD40 Antigens↗
PubMed2002

The autosomal recessive hypercholesterolemia (ARH) protein interfaces directly with the clathrin-coat machinery.

The low density lipoprotein (LDL) receptor plays a pivotal role in cholesterol metabolism. Inherited mutations that disturb the activity of the receptor lead to elevations in plasma cholesterol levels and early-onset coronary atherosclerosis. Defects in either the LDL receptor or apolipoprotein B, the proteinaceous component of LDL particles that binds the LDL receptor, elevate circulating LDL-cholesterol levels in an autosomal-dominant fashion, with heterozygotes displaying values between homozygous and normal individuals. Rarely, similar clinical phenotypes occur with a recessive pattern of inheritance, and several genetic lesions in the autosomal recessive hypercholesterolemia (ARH) gene on chromosome 1 have been mapped in this class of patients. ARH has an N-terminal phosphotyrosine-binding (PTB) domain evolutionarily related to that found in Disabled-2 and numb, two endocytic proteins. PTB domains bind to the consensus sequence FXNPXY, corresponding to the internalization motif of the LDL receptor. We show here that in addition to the FXNPXY sequence, ARH binds directly to soluble clathrin trimers and to clathrin adaptors by a mode involving the independently folded appendage domain of the beta subunit. At steady state, ARH colocalizes with endocytic proteins in HeLa cells, and the LDL receptor fluxes through peripheral ARH-positive sites before delivery to early endosomes. Because ARH also binds directly to phosphoinositides, which regulate clathrin bud assembly at the cell surface, our data suggest that in ARH patients, defective sorting adaptor function in hepatocytes leads to faulty LDL receptor traffic and hypercholesterolemia.

Adaptor Proteins, Signal Transducing↗
PubMed1983

Carbonic anhydrase II deficiency identified as the primary defect in the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification.

The clinical, radiological, and pathological findings in three siblings affected with the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification have been reported. In an effort to explain the pleiotropic effects of the mutation producing this disorder, we postulated a defect in carbonic anhydrase II (CA II), the only one of the three soluble isozymes of carbonic anhydrase that is known to be synthesized in kidney and brain. We report here biochemical and immunological evidence for the virtual absence of CA II in erythrocytes of patients affected with this condition, whereas CA I level is not reduced. Levels of CA II in erythrocyte hemolysates from asymptomatic obligate heterozygotes are about half of normal. These findings: (i) elucidate the basic defect in one form of inherited osteopetrosis; (ii) provide genetic evidence implicating CA II in osteoclast function and bone resorption; (iii) explain previous observations that carbonic anhydrase inhibitors block the normal parathyroid hormone-induced release of calcium from bone; (iv) clarify the role of renal CA II in urinary acidification and bicarbonate reabsorption; and (v) suggest a method to identify heterozygous carriers for the gene for this recessively inherited syndrome.

Acidosis, Renal Tubular↗
PubMed2001

Bilateral recession-resection surgery for convergent strabismus fixus associated with high myopia.

The authors report two patients with more than 20 diopters of myopia, severely restricted abduction, and more than 90Delta of acquired esotropia. Marked axial elongation of the globes was present. Each underwent large bilateral medial rectus recessions and bilateral lateral rectus resections. The deviations were significantly reduced and abduction improved with combined horizontal recession-resection surgery on both eyes.

Esotropia↗
PubMedDate not supplied

Osteoclast morphology in autosomal recessive malignant osteopetrosis due to a TCIRG1 gene mutation.

Bone biopsies were performed before and 7 weeks after transplantation of HLA-compatible bone marrow from the sister of a 3-month-old male infant with malignant autosomal recessive osteopetrosis due to a mutation in the TCIRG1 (ATP6i) gene. The first biopsy showed broad, immature bony trabeculae and no medullary hematopoiesis. Only few osteoclasts were present and electron microscopy showed absence of ruffled borders. The post transplant biopsy revealed donor osteoclasts with ruffled borders and intracytoplasmic mineral crystals as proof of active bone resorption that had not yet been detectable radiographically. Osteopetrosis is a genetically heterogeneous disease. Definition at the DNA-level will enable comparison of treatment strategies and prenatal diagnosis. As shown in this patient, the autosomal recessive form caused by a TCIRG1 gene mutation may be amenable to bone marrow transplantation. Activity of donor osteoclasts can be demonstrated morphologically on biopsy, before bone remodeling becomes evident radiologically.

Bone Marrow↗
PubMed1994

Recessive mutations in a common pathway block thymocyte apoptosis induced by multiple signals.

The glucocorticoid receptor (GR) is a ligand-regulated transcription factor that controls genes necessary to initiate glucocorticoid-induced thymocyte apoptosis. We have performed a genetic analysis of thymocyte cell death by isolating and characterizing a panel of GR+ dexamethasone-resistant mutants of the murine WEHI7.2 thymocyte cell line. These apoptosis-defective (Apt-) mutants were used to identify previously unknown early steps in the apoptotic pathway. The Apt- mutants contain nonglucocorticoid receptor, recessive mutations in genes that represent multiple complementation groups. These mutations block apoptosis induced by dexamethasone, gamma irradiation, and c-AMP treatment before the point where Bcl-2 exerts its protective effect. We propose that different signals share a common apoptotic pathway, and that the induction of apoptosis involves multiple precommitment steps that can be blocked by recessive mutations.

Animals↗
PubMed2006

A new autosomal recessive form of Stickler syndrome is caused by a mutation in the COL9A1 gene.

Stickler syndrome is characterized by ophthalmic, articular, orofacial, and auditory manifestations. It has an autosomal dominant inheritance pattern and is caused by mutations in COL2A1, COL11A1, and COL11A2. We describe a family of Moroccan origin that consists of four children with Stickler syndrome, six unaffected children, and two unaffected parents who are distant relatives (fifth degree). All family members were clinically investigated for ear, nose, and throat; ophthalmologic; and radiological abnormalities. Four children showed symptoms characteristic of Stickler syndrome, including moderate-to-severe sensorineural hearing loss, moderate-to-high myopia with vitreoretinopathy, and epiphyseal dysplasia. We considered the COL9A1 gene, located on chromosome 6q13, to be a candidate gene on the basis of the structural association with collagen types II and XI and because of the high expression in the human inner ear indicated by cDNA microarray. Mutation analysis of the coding region of the COL9A1 gene showed a homozygous R295X mutation in the four affected children. The parents and four unaffected children were heterozygous carriers of the R295X mutation. Two unaffected children were homozygous for the wild-type allele. None of the family members except the homozygous R295X carriers had any signs of Stickler syndrome. Therefore, COL9A1 is the fourth identified gene that can cause Stickler syndrome. In contrast to the three previously reported Stickler syndrome-causing genes, this gene causes a form of Stickler syndrome with an autosomal recessive inheritance pattern. This finding will have a major impact on the genetic counseling of patients with Stickler syndrome and on the understanding of the pathophysiology of collagens. Mutation analysis of this gene is recommended in patients with Stickler syndrome with possible autosomal recessive inheritance.

Child↗