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At least 19 recordsLinked to original sources
PubMed1992

Completeness of catalogs of autosomal dominant, autosomal recessive, and X-linked phenotypes.

The completeness of McKusick's catalogs of Mendelian Inheritance in Man (MIM) as to the number of phenotypes included was studied by estimating the degree of concordance with the Dutch Gene Catalog of the Department of Medical Genetics of the University of Groningen, The Netherlands. On a total of 355 Mendelian phenotypes described in persons living in The Netherlands or originating from this country, there were nine disease entities which were not present in MIM. As judged from this comparison MIM attains 97.5% completeness (95% CI: 95.3-98.7%). Similar comparisons with data from other countries are needed before a final conclusion can be reached. Corresponding contributors in different countries or linguistic areas might further improve MIM's completeness.

Catalogs as Topic↗
PubMed2000

Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy.

Emery-Dreifuss muscular dystrophy (EMD) is a condition characterized by the clinical triad of early-onset contractures, progressive weakness in humeroperoneal muscles, and cardiomyopathy with conduction block. The disease was described for the first time as an X-linked muscular dystrophy, but autosomal dominant and autosomal recessive forms were reported. The genes for X-linked EMD and autosomal dominant EMD (AD-EMD) were identified. We report here that heterozygote mutations in LMNA, the gene for AD-EMD, may cause diverse phenotypes ranging from typical EMD to no phenotypic effect. Our results show that LMNA mutations are also responsible for the recessive form of the disease. Our results give further support to the notion that different genetic forms of EMD have a common pathophysiological background. The distribution of the mutations in AD-EMD patients (in the tail and in the 2A rod domain) suggests that unique interactions between lamin A/C and other nuclear components exist that have an important role in cardiac and skeletal muscle function.

Adolescent↗
PubMed1985

Meatal atresia and hearing loss. Autosomal dominant and autosomal recessive inheritance.

Thirty-six ears of 33 patients with a type II unilateral or bilateral meatal atresia were accepted for reconstructive surgery. Five families of these patients had a history of congenital aural atresia. In one the father and his son had unilateral microtia. Four families counted 2 affected sibs each. The autosomal dominant and autosomal recessive patterns of inheritance are discussed.

Deafness↗
PubMed2001

Can progression of autosomal dominant or autosomal recessive polycystic kidney disease be prevented?

Data from animal and human studies suggest that the rate of progression of renal insufficiency can be retarded with careful control of blood pressure, institution of a low-protein diet, and the use of lipid-lowering agents. These therapeutic interventions become important when managing patients with renal insufficiency secondary to autosomal dominant polycystic kidney disease (PKD) and autosomal recessive polycystic kidney disease, in which end-stage renal disease is present in nearly 17,000 individuals per year. Several dietary and pharmacologic intervention strategies including blood pressure control, dietary modification, and the use of antioxidants as well as lipid-lowering agents have been studied in humans and animals with PKD in an effort to slow the rate of renal progression. This article reviews the current understanding of the effectiveness of these conventional therapies, as well as novel therapies that specifically target the mediators of cyst formation in PKD using tyrosine kinase inhibitors and gene therapy in an effort to identify potential strategies for retarding cyst formation and parenchymal injury in PKD. Current pharmacologic and dietary strategies fail to show any consistent benefits in preserving renal function and reducing renal injury in human PKD. The therapeutic potential for exciting new gene therapies and pharmacologic agents designed to target the pathophysiologic pathways involved in cyst formation are promising. Randomized, controlled trials in children and adults with early PKD are necessary to evaluate the effectiveness of these therapeutic interventions.

Animals↗
PubMed1995

The myotubular myopathies: differential diagnosis of the X linked recessive, autosomal dominant, and autosomal recessive forms and present state of DNA studies.

Clinical differences exist between the three forms of myotubular myopathy. They differ regarding age at onset, severity of the disease, and prognosis, and also regarding some of the clinical characteristics. The autosomal dominant form mostly has a later onset and milder course than the X linked form, and the autosomal recessive form is intermediate in both respects. These differences are, however, quantitative rather than qualitative. Muscle biopsy studies of family members are useful in some cases, and immunohistochemical staining of desmin and vimentin may help distinguish between the X linked and autosomal forms. Determining the mode of inheritance and prognosis in individual families, especially those with a single male patient, still poses a problem. Current molecular genetic results indicate that the gene for the X linked form is located in the proximal Xq28 region. Further molecular genetic studies are needed to examine the existence of genetic heterogeneity in myotubular myopathy and to facilitate diagnosis.

DNA↗
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↗
PubMed1983

[Temperature-sensitive autosomal dominant lethal mutations in Drosophila melanogaster induced by ethylmethane sulfonate].

Cold- and heat-sensitive dominant autosome and recessive sex-linked lethals were scored using C(1)RM, y; vg bw; e ss tester stock. The frequencies of heat-sensitive mutations were 1.43, 0.30, 0.07% and of cold-sensitive ones were 0.39, 0.16 and 0.09% in the 1-st, 2-nd and 3-rd chromosomes, respectively. For the first time, dominant cold-sensitive lethals were obtained in chromosome 3. The data from genetic analysis point to the fact that penetrance of such mutations strongly depends on the genetic background. That may be the reason, why they were not obtained using some of the balancer-3 chromosomes. Also, "cryptic" dominant autosome mutants were found which were not conditional but only revealed in the F2 generation. Their possible origin as gonado-somatic mosaics is discussed.

Animals↗
PubMedDate not supplied

[Cerebral arteriopathy with subcortical infarctions and leukoencephalopathy with dominant autosomal inheritance (CADASIL). Clinical and morphological study].

OBJECTIVE: The cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by the recurrence of subcortical infarcts leading to dementia. It is known the genetic and neuroimaging findings, but there are few studies about its histopathology. Our objective had been to study the pathological findings in this arteriopathy. SUBJECTS AND METHODS: We studied two families spreading over four generations. We performed a detailed clinical history, laboratory investigations, neuroimaging study and genetic analysis. Two brain biopsies and one autopsy were done in patients from the two families. RESULTS: Eight affected members, with autosomal dominant inheritance. Age at onset was between 40 and 50 years. This was characterized clinically by recurrent ischemic attacks, headache and subcortical dementia without vascular risk factors. Histopathological findings showed an arteriopathy characterized by a slightly basophilic small arterial granular degeneration of the medial sheath associated with the presence of ballooned smooth muscle cells with clear cytoplasm. CONCLUSION: The histopathological findings of CADASIL show a characteristic arteriopathy that allow a better understanding of its pathogenesis and could contribute for its diagnosis.

Adult↗
PubMed2005

A novel mutation (E767K) in the second extracellular loop of the calcium sensing receptor in a family with autosomal dominant hypocalcemia.

Autosomal dominant hypocalcemia resulting from gain-of-function mutations of the calcium sensing receptor (CASR) is a rare familial disorder that can become evident at any age. We report a novel mutation (E767K) of the CASR in a family with autosomal dominant hypocalcemia. Ten members of the family had a history of hypocalcemia. The index case exhibited marked hypocalcemia and seizures in the newborn period, while her father who also has hypocalcemia, was largely asymptomatic except for a myocardial infarction-like event at 21 years of age, a new presentation of the disorder. The E767K mutation, which resides in the second extracellular loop adjacent to the fifth transmembrane domain, co-segregated with hypocalcemia in these two individuals. Both subjects are heterozygous for the mutation. The proband is also heterozygous for the previously reported CASR polymorphism of G990R in the intracellular domain, while her father is homozygous. The co-segregation of this naturally occurring mutation with autosomal dominant hypocalcemia supports the previously reported experimental model in which it was proposed that the three acidic residues (767, 758, and 759) in exo-loop 2 in CASR help maintain an inactive conformation of the receptor.

Base Sequence↗
PubMed1993

[Current situation of dominant autosomal renal polycystosis].

Adult onset polycystic kidney disease causes 11% of all end-stage renal disease in Spain. Recent advantages in the molecular genetics of autosomal dominant polycystic kidney disease (ADPKD) point the way towards the cloning and decoding. One of the gene loci, namely PKD1, was located to the short arm of chromosome 16. Recombinants between 16p polimorphic loci and the PKD1 locus are described. The clinical consecuents of ADPKD are analyzed. Hypertension arterial are found more frequent in the those patients. Caution is therefore recommend in using ACE inhibitors who are at high risk because of compromised renal function. Our study clarifies several clinical extrarenal manifestations of ADPKD. All modalities of renal replacement therapy are appropriate therapeutics choices.

Humans↗
PubMedDate not supplied

[Heterozygosity loss and somatic mutations in type I and II dominant autosomal renal polycystic kidney disease: evidence of a recessive mechanism at a cell level in cystogenesis].

Autosomal dominant polycystic kidney disease (ADPKD) is a systemic disorder mainly characterized by renal cyst formation. Cysts in ADPKD are focal in nature, since only a small fraction of nephrons become cystic. The hypothesis that a second hit may be required for cyst formation has been proposed. This hypothesis suggests that inactivation of the inherited wild-type allele by a somatic mutation triggers cyst formation. In some cases, this second hit eliminates the normal allele and the affected cells remain with a single allele, which is the inherited mutated copy, and we only visualize one allele after the amplification by polymerase chain reaction; this is called loss of heterozygosity (LOH). In this study we have analysed the DNA isolated from epitehlial cells from 164 cysts of 8 kidneys affected by ADPKD type I and 30 cysts form a kidney affected by ADPKD type II. We have demonstrated the presence of LOH in 20.1% of PKD1 cysts and in 10% of PKD2 cysts. We have also found eight other different mutations in PKD2 cysts without LOH; so the percentage of somatic mutations in the PKD2 kidney reaches 36.6% of cysts. In conclusion, our data suggest that a recessive mechanism at the cellular level is implicated in cyst formation in the PKD1 and the PKD2 disease. The loss of both copies of the gene triggers the proliferation of a single cell, resulting in the cyst formation.

Chromosomes, Human, Pair 16↗
PubMedDate not supplied

[Mutational analysis of the PKD1 and PKD2 (type 1 and 2 dominant autosomal polycystic kidney) genes].

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. It is caused by mutations in at least two different genes: PKD1 and PKD2. The study of mutations in these genes is very difficult nowadays. In this study we have analyzed the non reiterated region of the PKD1 gene and all the exons and intron exon boundaries of the PKD2 gene. The technique used to study these genes have been single strand conformation analysis and heteroduplex. We have found 25 differences within the DNA sequence of the PKD1 gene with respect to the published sequence. Seven of these changes correspond to nonsense, missense, frameshifting and splicing mutations. The rest of changes correspond to polymorphisms or rare DNA variants. In the PKD2 gene we have identified 8 new mutations and one polymorphism. Six of these mutations are frameshifting, one is missense and the other one is a large deletion of the PKD2 gene. The rate of mutation detection within the PKD1 gene has been 4% and the rate for PKD2 has been 100%. We have not observed any correlation between genotype and phenotype either in the PKD1 nor in the PKD2 gene. The mutation analysis of ADPKD genes is very difficult, specially for the PKD1 gene. The rate of mutation detection is higher in the PKD2 gene but the global efficacy of the technique is very low as PKD2 represents only 15% of ADPKD patients. Nowadays linkage analysis is still the most useful technique for the molecular diagnosis of ADPKD patients.

DNA Mutational Analysis↗
PubMed1996

Periodic vestibulocerebellar ataxia, an autosomal dominant ataxia with defective smooth pursuit, is genetically distinct from other autosomal dominant ataxias.

BACKGROUND: Periodic vestibulocerebellar ataxia is an autosomal dominant disorder characterized by defective smooth pursuit, gaze-evoked nystagmus, ataxia, and vertigo. The age of onset ranges from the third to the sixth decade. To date, all patients have originated from North Carolina, suggesting a single common founder. OBJECTIVE: To clarify the classification of periodic vestibulocerebellar ataxia by determining whether it is allelic to other autosomal dominant cerebellar ataxias for which genes have been either localized or identified. METHODS: Blood was collected and DNA isolated from 66 subjects (19 affected individuals) in two multigenerational families. The microsatellite markers used in the analysis either flanked or were tightly linked to the disease gene regions. Two-point and multipoint linkage analyses were performed to define the limits of exclusion. RESULTS: Periodic vestibulocerebellar ataxia was excluded from loci linked to spinocerebellar ataxia type 1 (chromosome 6p), type 2 (chromosome 12q) type 3/Machado/Joseph disease (chromosome 14q), type 4 (chromosome 16q), and type 5 (11cent) as well as to episodic ataxia with myokymia (chromosome 12p), episodic ataxia with nystagmus (chromosome 19p), acetazolamide-responsive hereditary paroxysmal cerebellar ataxia (chromosome 19p), and dentatorubral-pallidoluysian atrophy/Haw River syndrome (chromosome 12p). CONCLUSION: Periodic vestibulocerebellar ataxia is genetically distinct from those autosomal dominant ataxias for which chromosomal localization has been established.

Alleles↗
PubMed2005

A novel pattern of mutation in uromodulin disorders: autosomal dominant medullary cystic kidney disease type 2, familial juvenile hyperuricemic nephropathy, and autosomal dominant glomerulocystic kidney disease.

BACKGROUND: Autosomal dominant medullary cystic kidney disease type 2 (MCKD2), familial juvenile hyperuricemic nephropathy (FJHN), and autosomal dominant glomerulocystic kidney disease (GCKD) constitute a hereditary renal disease group that may lead to end-stage renal failure caused by mutations of the UMOD gene and its product, uromodulin or Tamm-Horsfall protein. Of 34 different UMOD mutations described to date, 28 were located in exon 4. Based on such mutation clustering, some investigators have proposed that the sequencing of UMOD exon 4 might become a preliminary diagnostic test for patients with this phenotype. METHODS: We performed linkage analysis and sequencing of the entire codifying region of the UMOD gene in 4 Spanish families with MCKD/FJHN/GCKD. RESULTS: All families were shown to present mutations in the UMOD gene. In 3 families, the detected mutations were located in exon 5. Although 1 novel mutation (Gln316Pro) was observed in 2 of these families, a previously reported mutation (Cys300Gly) was found in the other kindred. The Cys300Gly mutation was found in the family presenting with a GCKD phenotype. CONCLUSION: Our data show a novel mutation pattern in UMOD , suggesting that exon 5 mutations can be more frequent in some populations. Our results support that every exon of the UMOD gene must be included in molecular testing and provide additional evidence for the existence of a fourth calcium-binding epidermal growth factor-like domain in the structure of Tamm-Horsfall protein. A second family reported to date is described, confirming that the GCKD phenotype may be caused by a UMOD mutation.

Adult↗
PubMed1977

Autosomal dominant osteosclerosis.

Autosomal dominant osteosclerosis, an entity previously labelled by various names, is clearly separate from Van Buchem disease; Van Buchem disease exhibits autosomal recessive inheritance. The clinical manifestation of autosomal dominant osteosclerosis is a widened and deepened mandible with increased gonial angle. Radiographic manifestations include endosteal sclerosis of the neurocranium with loss of the diploë, osteosclerosis and hyperostosis of the mandible with absence of the normal antegonial notches, endosteal sclerosis of the diaphyses of long bones (including metacarpals and metatarsals), and osteosclerosis of the pelvis.

Chromosome Aberrations↗
PubMed2005

Dominant negative mechanism underlies autosomal dominant Stargardt-like macular dystrophy linked to mutations in ELOVL4.

ELOVL4 (elongation of very long chain fatty acids 4) is a member of the ELO family of proteins involved in the biosynthesis of very long chain fatty acids. Protein truncation mutations in ELOVL4 have been identified in patients with autosomal dominant Stargardt-like macular degeneration. To determine whether a dominant negative mechanism is responsible for the autosomal dominant inheritance pattern of this disease, we studied the subcellular localization and interaction of wild type and mutant ELOVL4 in COS-7 and HEK 293T cultured cells by immunofluorescence and co-immunoprecipitation. Wild type ELOVL4 containing an endoplasmic reticulum retention sequence was localized to the endoplasmic reticulum as expected. In contrast, disease-associated C-terminal truncation ELOVL4 mutants accumulated as large inclusions exhibiting aggresome-like characteristics in a juxtanuclear position within COS-7 cells. When the wild type and mutant proteins were co-expressed incultured cells, wild type ELOVL4 co-purified with mutant ELOVL4 on an immunoaffinity column and co-localized with the mutant protein in aggresome-like inclusions adjacent to the nucleus. These results indicate that wild type and mutant ELOVL4 form a complex that exhibits an abnormal subcellular localization found for individually expressed mutant ELOVL4. From these studies, we conclude that disease-linked C-terminal truncation mutants of ELOVL4 exert a dominant negative effect on wild type ELOVL4, altering its subcellular localization. This dominant negative mechanism contributes to the autosomal dominant inheritance of Stargardt-like macular dystrophy.

Amino Acid Motifs↗