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At least 217 records · Page 12Linked to original sources
PubMed2006

Recessive cornea plana in the Kingdom of Saudi Arabia.

OBJECTIVE: To characterize the molecular genetics of clinically diagnosed recessive cornea plana in the Kingdom of Saudi Arabia and establish the presence of common or limited founders (ancestors who originally harbored the disease-causing mutation) in the country's historically isolated population. DESIGN: Prospective interventional case series. PARTICIPANTS: Twelve affected patients from apparently unrelated Saudi Arabian nuclear families with clinically diagnosed recessive cornea plana. METHODS: Clinical ophthalmic examination and venous blood sampling for DNA sequencing. MAIN OUTCOME MEASURES: Age, gender, keratometry, best-corrected visual acuity, ocular alignment, cycloplegic refraction, significant findings of a complete ophthalmic examination, and keratocan gene (KERA) haplotype analysis. RESULTS: All 12 individuals had classic phenotypic features of recessive cornea plana and were homozygous for 1 of 2 KERA mutations--a novel frameshift mutation (1634delC) or a previously reported nonsense mutation (R313X). Haplotype analysis was consistent with a separate distinct common founder effect for each instance. An additional Saudi KERA mutation (R279X) has been reported previously in one family. CONCLUSION: Specific for mutation in KERA, the ophthalmic phenotype of recessive cornea plana does not significantly vary with different KERA mutations. The occurrence of a rare inherited disease in a historically isolated population is not always due to a single common founder effect; it may be explained by cultural preferences such as consanguinity (intrafamilial marriage) and endogamy (intratribal marriage), which enhance expression of recessively inherited diseases.

Adolescent↗
PubMed1988

Protease inhibitor therapy for recessive dystrophic epidermolysis bullosa. In vitro effect and clinical trial with camostat mesylate.

Recently we reported that a kind of serine protease, SH protease, and collagenase might be involved in blister formation and, furthermore, that the cooperative action of these three proteases was essential for blister formation in recessive dystrophic epidermolysis bullosa. In this study we examined the inhibitory effect of clinically usable serine protease inhibitors for blister formation in organ culture and in clinical trials of recessive dystrophic epidermolysis bullosa patients. Camostat mesylate, a synthetic serine protease inhibitor that is available for the treatment of chronic pancreatitis, demonstrated a striking effect of inhibiting blistering in organ culture of normal human skin with recessive dystrophic epidermolysis bullosa blister fluids. Subsequently we administered camostat mesylate by topical application to four patients with recessive dystrophic epidermolysis bullosa to assess its ability to reduce blistering. Therapeutic response was favorable; a significant effect in decreasing the number of blisters was observed in three of four patients. These findings actually supported the hypothesis that a kind of serine protease had a close relationship with blistering in recessive dystrophic epidermolysis bullosa and that therapy with a clinically usable protease inhibitor was useful for the treatment of this disease.

Administration, Topical↗
PubMed2001

Evaluation of the dystrophin-glycoprotein complex, alpha-actinin, dysferlin and calpain 3 in an autosomal recessive muscular dystrophy in Labrador retrievers.

Labrador retrievers suffer from an autosomal recessive muscular dystrophy of unknown aetiology. Dogs affected with this disease develop generalized weakness associated with severe, generalized skeletal muscle atrophy and mild elevations in creatine kinase in the first few months of life. The severity of signs tends to progress over the first year of life but can vary from mild exercise intolerance to non-ambulatory tetraparesis. Beyond 1 year of age, the signs usually stabilize and although muscle mass does not increase, affected dogs' strength may improve slightly. The pathological changes present on muscle biopsy include marked variation in muscle fibre size with hypertrophied and round atrophied fibres present. There is an increased number of fibres with central nuclei and split fibres can be seen. It has been suggested that the disorder is a model for limb-girdle muscular dystrophy. In recent years, mutations in genes encoding the proteolytic enzyme, calpain 3, a novel protein named dysferlin, and components of the dystrophin-glycoprotein complex have been identified as causes of autosomal recessive limb-girdle muscular dystrophy. We have evaluated these proteins in normal dogs and in three Labrador retrievers with autosomal recessive muscular dystrophy using immunohistochemistry and Western blot analysis on frozen skeletal muscle. The results demonstrate that dystrophin, the sarcoglycans, alpha-actinin, dysferlin and calpain 3 are present in the normal and affected dogs. We conclude that this autosomal recessive muscular dystrophy is not due to a deficiency of alpha-actinin, or any of the known autosomal recessive limb-girdle muscular dystrophy proteins, although we cannot rule out a malfunction of any of these proteins.

Actinin↗
PubMed2003

The phenotypic manifestations of autosomal recessive axonal Charcot-Marie-Tooth due to a mutation in Lamin A/C gene.

Charcot-Marie-Tooth disease constitutes a genetically heterogeneous group of hereditary motor and sensory peripheral neuropathies. The axonal type of Charcot-Marie-Tooth is designated type 2. Six loci for autosomal dominant and three for recessive Charcot-Marie-Tooth type 2 have been reported so far. In this study we report the phenotype of autosomal recessive axonal Charcot-Marie-Tooth type 2 due to a recently-described mutation (c.892C>T-p.R298C) in a gene encoding Lamin A/C nuclear envelope proteins and the first gene in which a mutation leads to autosomal recessive Charcot-Marie-Tooth type 2. We have explored eight patients from four Algerian families. The onset is usually in the second decade and the course is rapid, involving upper limbs and proximal muscles, leading to a severe condition in less than 4 years. Many different mutations in Lamin A/C have been identified as causing variable phenotypes, such as limb girdle muscular dystrophy type 1B, autosomal dominant and recessive Emery-Dreyfuss muscular dystrophy, dilated cardiomyopathy with atrioventricular conduction defect, and Dunnigan-type familial partial lipodystrophy should prompt us to fully investigate the skeletal and cardiac muscles in patients affected with autosomal recessive Charcot-Marie-Tooth type 2 carrying a mutation in LMNA.

Algeria↗
PubMed2003

Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia.

Autosomal recessive progressive external ophthalmoplegia is a mitochondrial disease characterized by accumulation of multiple large-scale deletions of mitochondrial DNA. We previously reported missense mutations in POLG, the gene encoding the mitochondrial DNA polymerase gamma in two nuclear families compatible with autosomal recessive progressive external ophthalmoplegia. Here, we report a novel POLG missense mutation (R627W) in a sporadic patient and we provide genetic support that all these POLG mutations are actually causal and recessive. The novel patient presented with sensory ataxic neuropathy and has the clinical triad of sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO). This is the first finding of a genetic cause of Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoparesis and it implies that this disorder may actually be a variant of autosomal recessive progressive external ophthalmoplegia. Sensory neuropathy is the initial feature in Belgian compound heterozygote autosomal recessive progressive external ophthalmoplegia patients, all carrying the POLG A467T mutation, which occurs at a frequency of 0.6% in the Belgian population.

Adolescent↗
PubMed2003

Biochemical and recessive visible specific locus responses of C3H/HeH to fractionated, acute radiation.

The recessive visible specific locus test has been widely used for many years to investigate the genetic effects of radiation in mice. We devised an electrophoretic-specific locus test so that biochemical mutations leading to alterations in the activity or amount of four enzymes and proteins, as well as charge changes could be detected. We measured the yield of recessive visible and electrophoretic mutations in the same experiment so that a direct comparison of mutation incidence could be made. Dominant visible mutations were also scored. The recessive visible specific locus response of male C3H/HeH to a fractionated dose of 3 + 3 Gy X-irradiation separated by 24 h was similar to that previously reported for the F1 hybrid widely used in mutagenesis studies, and other strains. The response of C3H/HeH was significantly greater for the recessive visible mutations than for the biochemical mutations, supporting the contention that the recessive visible loci are more mutable than others. Mutational analysis of some of the mutants showed that the lesions ranged from a very deletion (30% of chromosome 14 deleted) to a point mutation. The number of loci scored in the electrophoretic test has been reassessed, and it is now considered that six, not four were scored, and this has implications for the calculation of the doubling dose.

Animals↗
PubMed2002

Periodontal plastic surgery for treatment of localized gingival recessions: a systematic review.

BACKGROUND: The evidence for the efficacy of periodontal plastic surgery (PPS) in the treatment of recession defects has not yet been systematically evaluated. The objective of this review was to systematically review the efficacy of PPS in achieving root coverage in the treatment of localized gingival recession. The following surgical procedures have been considered in this review: guided tissue regeneration (GTR), free gingival graft (FGG), connective tissue graft (CTG), and coronally advanced flap (CAF). METHODS: Randomized and controlled trials, as well as case series of at least 6 months' follow-up, were searched. Data sources included electronic databases and hand-searched journals. Screening, data abstraction and quality assessment were conducted independently and in duplicate. RESULTS: Regarding recession reduction, a limited but statistically significant greater benefit was found for CTG compared with GTR (weighted mean difference: 0.43 mm, 95% CI: 0.62-0.23). No differences were found comparing either GTR with CAF or resorbable versus non-resorbable GTR barriers. Gain in attachment was also similar for each of the three comparisons. Analysis of single arms of trials and case series demonstrated that PPS can have a marked improvement on clinical parameters but heterogeneity was often high and only partly explained by initial defect depth. CONCLUSIONS: Overall, PPS was effective in reducing gingival recessions with a concomitant improvement in attachment levels. Even though no single treatment can be considered superior to all the others, CTG was statistically significantly more effective than GTR in recession reduction. Further research is needed to identify the factors most associated with successful outcomes.

Connective Tissue↗
PubMed2001

Gingival recession defects and guided tissue regeneration: a review.

The last decade has seen an increasing number of clinical reports on guided tissue regeneration (GTR) for reconstruction of gingival recession defects. This article reviews the value of GTR in the management of gingival recession defects based on records from such reports. Studies and case-series using nonresorbable and bioresorbable membranes, studies comparing GTR to the subepithelial connective tissue graft (CTG) procedure, and histologic reports of healing following GTR, published in the English language from 1985 to 2000, were identified using a Medline search and were included in the data-base for this review. The Following pre- and post-treatment data were collated and evaluated for each of the reports: gingival recession depth, probing depth, clinical attachment level, and width of the keratinized gingiva. In perspective of the limitations of the studies reviewed, it has been shown that GTR may be used for reconstruction of gingival recession detects. Importantly it has not been shown that GTR provides an added clinical benefit for the patient treatment planned for reconstruction of gingival recession defects. i.e. GTR does not appear to offer a significant advantage over mucogingival procedures such as the connective tissue graft or the advanced flap procedure. It is imperative to recognize inherent technical difficulties associated with GTR including primary would closure and secondary membrane exposure: membrane exposures being negatively correlated to desired clinical outcomes. Also, membrane exposures appear consistently more common in smokers than in non-smokers. It is also imperative to recognize shortcomings and adverse effects including space maintenance and unacceptable foreign body reactions associated with some bioresorbable GTR technologies.

Absorbable Implants↗
PubMed2006

Mutations in SYNE1 lead to a newly discovered form of autosomal recessive cerebellar ataxia.

The past decade has seen great advances in unraveling the biological basis of hereditary ataxias. Molecular studies of spinocerebellar ataxias (SCA) have extended our understanding of dominant ataxias. Causative genes have been identified for a few autosomal recessive ataxias: Friedreich's ataxia, ataxia with vitamin E deficiency, ataxia telangiectasia, recessive spastic ataxia of Charlevoix-Saguenay and ataxia with oculomotor apraxia type 1 (refs. 6,7) and type 2 (ref. 8). Nonetheless, genes remain unidentified for most recessive ataxias. Additionally, pure cerebellar ataxias, which represent up to 20% of all ataxias, remain poorly studied with only two causative dominant genes being described: CACNA1A (ref. 9) and SPTBN2 (ref. 10). Here, we report a newly discovered form of recessive ataxia in a French-Canadian cohort and show that SYNE1 mutations are causative in all of our kindreds, making SYNE1 the first identified gene responsible for a recessively inherited pure cerebellar ataxia.

Adult↗
PubMed2003

Skin expression of metalloproteinases and tissue inhibitor of metalloproteinases in sibling patients with recessive dystrophic epidermolysis and intrafamilial phenotypic variation.

A number of COL7A1 mutations have now been reported in recessive dystrophic epidermolysis bullosa patients, and the analysis of phenotype-genotype correlations showed evidence for interfamilial and intrafamilial phenotypic variability, occurring for the same mutation. Collagenase and stromelysin activities have been found to be overexpressed in skin cultures of some recessive dystrophic epidermolysis bullosa patients, and tissue destruction in the disease process might result from an imbalance of metalloproteinases (MMP) over tissueinhibitor of metalloproteinases (TIMP). So we suspected that the phenotypic variability for the same mutation could be linked to other genetic or environmental factors, as a particular balance between MMP and TIMP. Organ cultures were performed using explants from the skin of three patients from the same family with recessive dystrophic epidermolysis bullosa to reveal and quantify the expression of MMP-1 (collagenase 1), MMP-2 and MMP-9 (gelatinases A and B), MMP-3 (stromelysin 1), TIMP-1, and TIMP-2, and to compare the results with those obtained with two human control skins, with the same experimental conditions. Increased amounts of all metalloproteinases investigated were observed in the skin of the three recessive dystrophic epidermolysis bullosa affected sibling brothers, both in lesioned and in apparently nonlesioned skin, compared with controls. The amounts of MMP-1, MMP-2, MMP-3, and MMP-9 increased particularly in the skin of the more clinically affected patient. Furthermore for this patient we evidenced higher amounts of MMP-1 and also a lower TIMP-1 amount in his unlesioned and lesioned skin compared with the other two affected patients and with healthy control donors. So we can suspect that recessive dystrophic epidermolysis bullosa phenotypic variability could be related to patients' collagenase activity heterogeneity, linked to imbalance between MMP-1 and TIMP-1.

Adolescent↗
PubMedDate not supplied

Human red cell antigens. V. Expression of In(Lu)-related p80 antigens by recessive-type Lu(a-b-) red cells.

The In(Lu) gene, which inhibits the expression of Lutheran blood group antigens by red cells (RBCs), also down-regulates the expression of an 80-kD glycoprotein, In(Lu)-related p80, by both RBCs and a subset of white cells. This study examined the expression of multiple-RBC p80 epitopes by autosomal and X-linked recessive-type Lu(a-b-) RBCs in order to explore the relationship, if any, between expression of In(Lu)-related p80 and Lutheran antigens. Both autosomal and X-linked types of recessive Lu(a-b-) RBCs expressed near-normal to increased amounts of p80 antigens, as measured by radioimmunoassay. P80 from both types of recessive Lu(a-b-) RBCs had apparently normal molecular weight in denaturing polyacrylamide gels and showed normal sensitivity to digestion by trypsin and chymotrypsin. Thus, the absence of Lutheran antigens on recessive-type Lu(a-b-) RBCs is not associated with decreased or absent p80 antigens. Furthermore, the XS2 gene probably does not act via a mechanism similar to that of the In(Lu) gene, since the expression of p80 remains undiminished in X-linked recessive-type Lu(a-b-) RBCs.

Genes, Recessive↗
PubMed1998

Mutations in the connexin 26 gene (GJB2) among Ashkenazi Jews with nonsyndromic recessive deafness.

BACKGROUND: Mutations in the GJB2 gene cause one form of nonsyndromic recessive deafness. Among Mediterranean Europeans, more than 80 percent of cases of nonsyndromic recessive deafness result from inheritance of the 30delG mutant allele of GJB2. We assessed the contribution of mutations in GJB2 to the prevalence of the condition among Ashkenazi Jews. METHODS: We tested for mutations in GJB2 in DNA samples from three Ashkenazi Jewish families with nonsyndromic recessive deafness, from Ashkenazi Jewish persons seeking carrier testing for other conditions, and from members of other ethnic groups. The hearing of persons who were heterozygous for mutations in GJB2 was assessed by means of pure-tone audiometry, measurement of middle-ear immittance, and recording of otoacoustic emissions. RESULTS: Two frame-shift mutations in GJB2, 167delT and 30delG, were observed in the families with nonsyndromic recessive deafness. In the Ashkenazi Jewish population the prevalence of heterozygosity for 167delT, which is rare in the general population, was 4.03 percent (95 percent confidence interval, 2.5 to 6.0 percent), and for 30delG the prevalence was 0.73 percent (95 percent confidence interval, 0.2 to 1.8 percent). Genetic-linkage analysis showed conservation of the haplotype for 167delT but the existence of several haplotypes for 30delG. Audiologic examination of carriers of the mutant alleles who had normal hearing revealed subtle differences in their otoacoustic emissions, suggesting that the expression of mutations in GJB2 may be semidominant. CONCLUSIONS: The high frequency of carriers of mutations in GJB2 (4.76 percent) predicts a prevalence of 1 deaf person among 1765 people, which may account for the majority of cases of nonsyndromic recessive deafness in the Ashkenazi Jewish population. Conservation of the haplotype flanking the 167delT mutation suggests that this allele has a single origin, whereas the multiple haplotypes with the 30delG mutation suggest that this site is a hot spot for recurrent mutations.

Connexin 26↗
PubMed1998

Mutations in the chloride-bicarbonate exchanger gene AE1 cause autosomal dominant but not autosomal recessive distal renal tubular acidosis.

Primary distal renal tubular acidosis (dRTA) is characterized by reduced ability to acidify urine, variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, and nephrolithiasis. Kindreds showing either autosomal dominant or recessive transmission are described. Mutations in the chloride-bicarbonate exchanger AE1 have recently been reported in four autosomal dominant dRTA kindreds, three of these altering codon Arg589. We have screened 26 kindreds with primary dRTA for mutations in AE1. Inheritance was autosomal recessive in seventeen kindreds, autosomal dominant in one, and uncertain due to unknown parental phenotype or sporadic disease in eight kindreds. No mutations in AE1 were detected in any of the autosomal recessive kindreds, and analysis of linkage showed no evidence of linkage of recessive dRTA to AE1. In contrast, heterozygous mutations in AE1 were identified in the one known dominant dRTA kindred, in one sporadic case, and one kindred with two affected brothers. In the dominant kindred, the mutation Arg-589/Ser cosegregated with dRTA in the extended pedigree. An Arg-589/His mutation in the sporadic case proved to be a de novo mutation. In the third kindred, affected brothers both have an intragenic 13-bp duplication resulting in deletion of the last 11 amino acids of AE1. These mutations were not detected in 80 alleles from unrelated normal individuals. These findings underscore the key role of Arg-589 and the C terminus in normal AE1 function, and indicate that while mutations in AE1 cause autosomal dominant dRTA, defects in this gene are not responsible for recessive disease.

Acidosis, Renal Tubular↗
PubMed1998

Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosis.

RPE65 is a protein of unknown function expressed specifically by the retinal pigment epithelium. We examined all 14 exons of this gene in 147 unrelated patients with autosomal recessive retinitis pigmentosa (RP), in 15 patients with isolate RP, and in 45 patients with Leber congenital amaurosis (LCA). Sequence anomalies that were likely to be pathogenic were found in two patients with recessive RP, in one patient with isolate RP recategorized as recessive, and in seven patients with LCA. Cosegregation analysis in each available family showed that all affected individuals were either homozygotes or compound heterozygotes and that all unaffected individuals were either heterozygote carriers or homozygous wild type. In one family, there was one instance of a new mutation not present in either parent of the affected individual. In another family, affected members with recessive RP in three branches (i.e., three distinct pairs of parents) were compound heterozygotes for the same two mutations or homozygous for one of them. Based on our results, mutations in the RPE65 gene appear to account for approximately 2% of cases of recessive RP and approximately 16% of cases of LCA.

Blindness↗
PubMed1999

Localization of a gene for autosomal recessive distal renal tubular acidosis with normal hearing (rdRTA2) to 7q33-34.

Failure of distal nephrons to excrete excess acid results in the "distal renal tubular acidoses" (dRTA). Early childhood features of autosomal recessive dRTA include severe metabolic acidosis with inappropriately alkaline urine, poor growth, rickets, and renal calcification. Progressive bilateral sensorineural hearing loss (SNHL) is evident in approximately one-third of patients. We have recently identified mutations in ATP6B1, encoding the B-subunit of the collecting-duct apical proton pump, as a cause of recessive dRTA with SNHL. We now report the results of genetic analysis of 13 kindreds with recessive dRTA and normal hearing. Analysis of linkage and molecular examination of ATP6B1 indicated that mutation in ATP6B1 rarely, if ever, accounts for this phenotype, prompting a genomewide linkage search for loci underlying this trait. The results strongly supported linkage with locus heterogeneity to a segment of 7q33-34, yielding a maximum multipoint LOD score of 8.84 with 68% of kindreds linked. The LOD-3 support interval defines a 14-cM region flanked by D7S500 and D7S688. That 4 of these 13 kindreds do not support linkage to rdRTA2 and ATP6B1 implies the existence of at least one additional dRTA locus. These findings establish that genes causing recessive dRTA with normal and impaired hearing are different, and they identify, at 7q33-34, a new locus, rdRTA2, for recessive dRTA with normal hearing.

Acidosis, Renal Tubular↗
PubMed1997

Definitive evidence for an autosomal recessive form of hypohidrotic ectodermal dysplasia clinically indistinguishable from the more common X-linked disorder.

A crucial issue in genetic counseling is the recognition of nonallelic genetic heterogeneity. Hypohidrotic (anhidrotic) ectodermal dysplasia (HED), a genetic disorder characterized by defective development of hair, teeth, and eccrine sweat glands, is usually inherited as an X-linked recessive trait mapped to the X-linked ectodermal dysplasia locus, EDA, at Xq12-q13.1. The existence of an autosomal recessive form of the disorder had been proposed but subsequently had been challenged by the hypothesis that the phenotype of severely affected daughters born to unaffected mothers in these rare families may be due to marked skewing of X inactivation. Five families with possible autosomal recessive HED have been identified, on the basis of the presence of severely affected females and unaffected parents in single sibships and in highly consanguineous families with multiple affected family members. The disorder was excluded from the EDA locus by the lack of its cosegregation with polymorphic markers flanking the EDA locus in three of five families. No mutations of the EDA gene were detected by SSCP analysis in the two families not excluded by haplotype analysis. The appearance of affected males and females in autosomal recessive HED was clinically indistinguishable from that seen in males with X-linked HED. The findings of equally affected males and females in single sibships, as well as the presence of consanguinity, support an autosomal recessive mode of inheritance. The fact that phenotypically identical types of HED can be caused by mutations at both X-linked and autosomal loci is analogous to the situation in the mouse, where indistinguishable phenotypes are produced by mutations at both X-linked (Tabby) and autosomal loci (crinkled and downless).

Adolescent↗
PubMed1980

Meiosis in Neurospora crassa. I. The isolation of recessive mutants defective in the production of viable ascospores.

A scheme has been devised for efficient isolation of recessive meiotic mutants of Neurospora crassa. These mutants were detected by their reduced fertility or by the abortion of ascospores. Their isolation involved the selection and screening of the strains arising from ascospores disomic (n + 1) for linkage group I (LG I), which bears the mating-type locus. These strains are self-fertile heterokaryons that contain two types of haploid nuclei of opposite mating types (A + a). Selfings of these strains are homozygous for genes on all linkage groups except LGI and therefore allow the expression of recessive mutants with an altered sexual cycle. Using this selection procedure, three classes of mutants were detected. In one class, mutants had an early block in perithecial development (class I), and in another mutants had altered perithecia, but apparently unaltered fertility (class III). No recessive mutants were observed and all mutants tested (eight of class I and two of class III) were expressed only when used as the maternal parent. A third mutant class displayed normal production of perithecia, but defective formation of asci (class IIA), or black ascospores (class IIB). Four of 13 class IIA mutants were analyzed, and two of them [asc(DL131) and asc (DL400)] were definitely recessive analysis of 10 of 13 class IIB mutants disclosed six recessive, mutually complementing mutants: ase(DL95), asc(DL243), asc(DL711), asc(DL879), asc(DL917m) and asc(DL961). Mutants asc(DL95), asc(DL243) and the previously studied mei-1 mutant (Smith 1975) complemented one another in crosses, but did not recombine. These may be alleles of the same gene, or they may comprise a gene cluster.

Crosses, Genetic↗
PubMed1997

Identification of functionally important regions of the muscular chloride channel CIC-1 by analysis of recessive and dominant myotonic mutations.

Mutations in the muscular voltage-dependent Cl-channel, CIC-1, lead to recessive and dominant myotonia. Here we analyse the effects of one dominant (G200R) and three recessive (Y150C, Y261C, and M485V) mutations after functional expression in Xenopus oocytes. Glycine 200 is a highly conserved amino acid located in a conserved stretch in the putatively cytoplasmic loop between domains D2 and D3. Similar to several other dominant mutations the amino acid exchange G200R leads to a drastic shift by approximately 65 mV of the open probability curve to more positive voltages. As explored by co-expression studies, the shift is intermediate in heteromeric mutant/WT channels. Open channel properties such as single channel conductance, rectification or ion selectivity are not changed. Thus we identified a new region of the CIC-1 protein in which mutations can lead to drastic shifts of the voltage dependence. The recessive mutation M485V, which is located in a conserved region at the beginning of domain D10, leads to a drastic reduction of the single channel conductance from 1.5 pS for WT to approximately 0.3 pS. In addition, the mutant is strongly inwardly rectifying and deactivates incompletely at negative voltages. Ion-selectivity, however, is unchanged. These electrophysiological properties fully explain the recessive phenotype of the mutation and identify a new region of the protein that is involved in ion permeation and gating of the CIC-1 channel. The other two recessive mutations (Y150C and Y261C) had been found in a compound heterozygous patient. Surprisingly, expression of these mutants in oocytes yielded currents indistinguishable from WT CIC-1 when explored by two-electrode voltage clamp recording and patch clamping (either singly or both mutations co-expressed). Other mechanisms that are not faithfully represented by the Xenopus expression system must therefore be responsible for the myotonic symptoms associated with these mutations.

Amino Acid Sequence↗