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Results for “Phenotypic variability”

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PubMed2003

LIS1 missense mutations: variable phenotypes result from unpredictable alterations in biochemical and cellular properties.

Mutations in one allele of the human LIS1 gene cause a severe brain malformation, lissencephaly. Although most LIS1 mutations involve deletions, several point mutations with a single amino acid alteration were described. Patients carrying these mutations reveal variable phenotypic manifestations. We have analyzed the functional importance of these point mutations by examining protein stability, folding, intracellular localization, and protein-protein interactions. Our data suggest that the mutated proteins were affected at different levels, and no single assay could be used to predict the lissencephaly phenotype. Most interesting are those mutant proteins that retain partial folding and interactions. In the case of LIS1 mutated in F31S, the cellular phenotype may be modified by overexpression of specific interacting proteins. Overexpression of the PAF-AH alpha1 subunit dissolved aggregates induced by this mutant protein and increased its half-life. Overexpression of NudE or NudEL localized this mutant protein to spindle poles and kinetochores but had no effect on protein stability. Our results implicate that there are probably different biochemical and cellular mechanisms obstructed in each patient yielding the varied lissencephaly phenotypes.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed1995

Fluorescence-based DNA fingerprinting elucidates nosocomial transmission of phenotypically variable Pseudomonas aeruginosa in intensive care units.

DNA fingerprinting based on automated laser fluorescence analysis of randomly amplified polymorphic DNA (RAPD-ALFA) is a rapid and convenient technique for detecting clonal relatedness of bacterial isolates of nosocomial concern. During an outbreak of Pseudomonas aeruginosa among five patients in a medical intensive care unit, transmission was not suspected because of the phenotypic variability of the initial isolates. However, DNA fingerprinting by RAPD-ALFA and macrorestriction analysis identified a single genotype (strain A) for isolates from three patients and another genotype (strain B) for isolates from the remaining two patients. Strain A isolates displayed three phenotypes defined by different antibiotypes and distinct colony appearance. Retrospective analysis of DNA fingerprints demonstrated that strain A had been transmitted to the index patient one year previously in a different intensive care unit. The study demonstrates that genetic typing approaches are warranted should epidemiological relatedness be identified between phenotypically variant pathogens. Automated laser fluorescence analysis of PCR fingerprints may facilitate routine screening of bacterial isolates for in-house epidemiological surveillance. Antibiograms are an unsuitable approach for the typing of Pseudomonas aeruginosa.

Adult↗

PubMed2006

Phenotypic variability of mitochondrial disease caused by a nuclear mutation in complex II.

We report a patient with relatively mild Leigh syndrome and mitochondrial respiratory chain complex II deficiency caused by a homozygous G555E mutation in the nuclear encoded flavoprotein subunit of succinate dehydrogenase. This mutation has previously been reported in a lethal-infantile presentation of complex II deficiency. Such marked phenotypic heterogeneity, although typical of heteroplasmic mutations in the mitochondrial genome, is unusual for nuclear mutations. Comparable activities and stability of mitochondrial respiratory chain enzymes were demonstrated in both patients, so other reasons for the phenotypic variability are considered.

Amino Acid Sequence↗

PubMed1991

Pseudohypoparathyroidism: its phenotypic variability and associated disorders in a large family.

Pseudohypoparathyroidism is a complex disorder of renal resistance to parathyroid hormone the mechanism of which is unclear. It is often associated with skeletal abnormalities and there may also be other hormonal defects. This is an extensive endocrinological investigation of five of six affected members in two generations of one family. The phenotypic variability of the syndrome is explored: four members had hypothyroidism; two had abnormal gonadal function; all five had abnormal prolactin response to TRH; one had abnormal hepatic response to glucagon infusion. All had normal hypothalamic-pituitary-adrenal axes, renal responsiveness to vasopressin and growth hormone responses to a variety of stimuli. Special note is made of oral pathology, and evidence of platelet aggregation abnormalities is presented which has not previously been described in the syndrome.

Adolescent↗

PubMed1992

Phenotypic variability of mannosidosis type II: report of two Greek siblings.

Two patients, a 13-year-old boy and his 24-year-old sister, were diagnosed as mannosidosis type II cases, on the basis of both presenting extremely reduced plasma and white blood cell acid-alpha-mannosidase are reported. With the exception of mental retardation and neurosensory deafness the two siblings manifested a wide phenotypic variability. The boy had several facial features indicating a lysosomal storage disorder, as well as spondylolisthesis. His sister, apart from heavy eyebrows and lower jaw prognathism appeared normal.

Adolescent↗

PubMed2004

Phenotypic variability in human embryonic holoprosencephaly in the Kyoto Collection.

BACKGROUND: Holoprosencephaly (HPE) is one of the most common developmental disorders of the brain associated with specific craniofacial dysmorphogenesis. Although numerous postnatal cases have been reported, early phases of its pathogenesis are not well understood. We examined over 200 cases of HPE human embryos both grossly and histologically, and studied their phenotypic variability and stage-specific characteristics. METHODS: Among over 44,000 human embryos in the Kyoto Collection of Human Embryos, 221 embryos have been diagnosed as HPE. Their developmental stages ranged from Carnegie stage (CS) 13 to CS 23. They were examined grossly and were also serially sectioned for detailed histological analysis. RESULTS: HPE embryos after CS 18 were classified into complete (true) cyclopia, synophthalmia (partially fused eyes in a single eye fissure), closely apposed separate eyes (possible forerunners of ethmocephaly and cebocephaly), and milder HPE with median cleft lip (premaxillary agenesis). At CS 13-17, when facial morphogenesis is not completed, HPE embryos had some facial characteristics that are specific to these stages and different from those in older HPE embryos. The midline structures of the brain, including the pituitary gland, were lacking or seriously hypoplastic in HPE embryos. Complete cyclopia was found in two cases after CS 18 but none at earlier stages. CONCLUSIONS: The early development of HPE in human embryos was systematically studied for the first time. The pathogenesis of craniofacial abnormalities, especially eye anomalies, in HPE was discussed in the light of recent studies with mutant laboratory animals.

Embryonic Development↗

PubMed2003

Dopamine beta-hydroxylase (DBH) gene and schizophrenia phenotypic variability: a genetic association study.

Recently, two polymorphisms (DBH5'-Ins/del and DBH 444 g/a) of the Dopamine Beta Hydroxylase (DBH) gene were isolated, and one haplotype (Del-a) was found to be associated with low DBH activity and cocaine-induced paranoia. The purpose of this study is to test for association between these two polymorphisms and schizophrenia or its phenotypic variability with respect to neuroleptic therapeutic response and symptom profile. Allelic and haplotype distributions of these two polymorphisms were compared between two groups of schizophrenic patients (excellent neuroleptic-responders; R, n = 42 and non-responders; NR, n = 64), and one group of healthy volunteers (n = 120). The "Del" and "a" alleles were in positive linkage disequilibrium. No allelic or genotype differences in the distribution of these two polymorphisms were observed between patients and controls. However, The Del-a haplotype was significantly more common in NR patients, and the mean total BPRS score was significantly higher in the group of patients with the Del-a compared to those without the Del-a haplotype. These results suggest that the DBH gene is not a causative factor in schizophrenia but that it may be a modulator of psychotic symptoms, severity of the disorder and therapeutic response to neuroleptic drugs.

Adolescent↗

PubMed2002

Phenotypic variability in a Spanish family with MNGIE.

Clinical, biochemical, and genetic features of a Spanish family with mitochondrial neurogastrointestinal encephalomyopathy are reported. The proband presented with severe gastrointestinal dysmotility and the affected sister had extraocular muscle weakness. In both affected individuals, biochemical defects of thymidine phosphorylase and a pathogenic G-to-A transition mutation at nucleotide 435 in the thymidine phosphorylase gene were identified. The first thymidine phosphorylase mutation identified in Spain showed phenotypic variability at onset.

Adult↗

PubMed2005

Multicystic dysplastic kidney and variable phenotype in a family with a novel deletion mutation of PAX2.

The renal coloboma syndrome (OMIM 120330) is caused by mutations in the PAX2 gene. Typical findings in these patients include renal hypoplasia, renal insufficiency, vesicoureteric reflux, and optic disc coloboma. A family with a novel heterozygous 10-bp deletion in exon 2 of the PAX2 gene leading to a truncating mutation and variable phenotype across three generations is reported. The first presentation of multicystic dysplastic kidney in this syndrome is reported. The possibility that abnormal PAX2 protein in this case may cause a dominant negative effect also is discussed. The finding of multicystic dysplastic kidney in renal coloboma syndrome could suggest that PAX2 may play a role in early ureteric obstruction and subsequent renal maldevelopment.

Adult↗

PubMed2006

Methionine metabolism and phenotypic variability in X-linked adrenoleukodystrophy.

A combined genotype of polymorphisms of methionine metabolism has been associated with CNS demyelination in methotrexate-treated patients. Within a sample of 86 patients with X-linked adrenoleukodystrophy, this genotype was overrepresented in a subgroup of 15 patients with adrenomyeloneuropathy (AMN) with CNS demyelination (adrenoleukomyeloneuropathy) in comparison to 49 AMN patients without CNS demyelination ("pure" AMN; p = 0.002), suggesting that methionine metabolism might contribute to the phenotypic variability in adrenoleukodystrophy.

Adolescent↗

PubMed2002

Intrafamilial phenotype variability in nephrogenic diabetes insipidus.

X-Linked nephrogenic diabetes insipidus (NDI), which accounts for 90% of inherited cases of NDI, is caused by mutations in the AVPR2 gene that encodes the arginine vasopressin (AVP) receptor type 2 (V2R). The V2R mediates the antidiuretic action of AVP in principal cells of the collecting duct. To date, only three AVPR2 mutations (P322S, D85N, and G201D) have been associated with a mild NDI phenotype, and intrafamilial phenotype variability has not been reported in affected males. We describe a novel Belgian family with X-linked NDI caused by substitution of a histidine for an arginine at position 137 (R137H) of AVPR2. This mutation has been identified in two brothers and their mother. The R137H mutation results in a failure of V2R to stimulate adenylate cyclase and has been associated consistently with severe NDI and the inability to increase urinary osmolality to greater than plasma osmolality during water deprivation and/or infusion of 1-desamino-8-d-arginine vasopressin. Detailed examination of the two affected brothers showed the typical NDI phenotype in the 45-year-old proband, whereas a milder clinical phenotype associated with significant urinary concentrating ability during water deprivation was documented in the 33-year-old brother. Thus, in this family, the R137H mutation is associated with either a mild or severe NDI phenotype. Mechanisms that might account for these findings include genetic and/or environmental modifiers.

Amino Acid Sequence↗

PubMed1977

Variable phenotypic expression of an X-linked recessive lymphoproliferative syndrome.

Investigation of a family with cancer in boys revealed that at least 20 males had the X-linked recessive lymphoproliferative syndrome. A variety of phenotypes occurred: aproliferative phenotypes consisted of aplastic anemia, agranulocytosis or acquired hypogammaglobulinemia; and proliferative phenotypes of B cells included disorders associated with the Epstein-Barr virus, American Burkitt's lymphoma, immunoblastic sarcoma of B cells, fatal infectious mononucleosis or plasmacytoma. The lymphoproliferative disorders observed in males could have resulted from an immunodeficiency to Epstein-Barr virus. The variable phenotypic expression could have resulted from individual differences in the viral dose, duration of exposure and age at which the boys were exposed to the virus. Aproliferative phenotypes such as acquired hypogammaglobulinemia could have ensued from excessive suppressor-cell activity on B cells, whereas proliferative phenotypes such as Burkitt's lymphoma or fatal infectious mononucleosis could have resulted from infection by Epstein-Barr virus and failure to stop proliferation of B cells.

Adolescent↗

PubMed2005

Benign familial infantile convulsions: phenotypic variability in a family.

Benign familial infantile convulsion is an autosomal dominant epilepsy syndrome characterized by seizures starting from 3 to 12 months and a favorable outcome. We present a Turkish family with benign familial infantile convulsions and report the clinical variability associated with this syndrome in three generations. All 11 affected members had benign infantile seizures, which were primarily generalized in all but one patient, who had partial seizures with secondary generalization. The seizures started within the first year and were accompanied by normal neurologic development and a good response to treatment with phenobarbital. In this family, the phenotype extended beyond infancy. The index patient had unilateral occipital spike and waves on electroencephalography (EEG), although he had no clinical seizures at 4 years of age. Follow-up EEG of this patient 1 year later showed that the discharges shifted to the occipital lobe of the other hemisphere. The grandmother of this patient had temporal lobe seizures as an adult, years after the remission of infantile convulsions. One of the patients experienced paroxysmal choreoathetosis during adolesence. Our findings highlight the intrafamilial phenotypic variability of benign familial infantile convulsions in a large pedigree with long-term follow-up.

Adolescent↗

PubMed1983

Variable phenotype associated with duplication of different regions of 2p.

Previous reports suggest that duplication of the distal part of 2p causes a distinct syndrome. Of the 20 published cases, all resulted from a parental translocation. We report here clinical and cytogenetic data on three patients with dup(2p) and few, if any, of the physical findings of the syndrome. Our data suggest that dup(2p) is associated with an extremely variable phenotype which may be quite mild in some cases. It is also possible that many of the nonspecific developmental anomalies thought to be part of the syndrome may be caused by the accompanying deletion.

Chromosome Aberrations↗

PubMed2001

Phenotypic variability of Cat-Eye syndrome.

Cat-Eye syndrome (CES) is a disorder with a variable pattern of multiple congenital anomalies of which coloboma of the iris and anal atresia are the best known. CES is cytogenetically characterised by the presence of an extra bisatellited marker chromosome, which represents an inverted dicentric duplication of a part of chromosome 22 (inv dup(22)). We report on three CES-patients who carry an inv dup(22) diagnosed with FISH studies. They show remarkable phenotypic variability. The cause of this variability is unknown. Furthermore, we review clinical features of 71 reported patients. Only 41% of the CES-patients have the combination of iris coloboma, anal anomalies and pre-auricular anomalies. Therefore, almost 60% of the CES-patients are hard to recognize by their phenotype alone. Mild to moderate mental retardation was found in 32% (16/50) of the cases. Mental retardation occurs more frequently in male CES-patients. There is no apparent phenotypic difference between mentally retarded and mentally normal CES-patients.

Abnormalities, Multiple↗

PubMed1994

Phenotypic variability of del(2) (q22-q23): report of a case with a review of the literature.

An interstitial deletion of 2q22-q23 was found in a 2.5 year old boy with multiple congenital abnormalities (including Hirschsprung's disease) and severe mental retardation. Comparison with seven additional cases of 2q deletions from the literature does not allow the delineation of a clinically recognizable syndrome. Some of the previously reported patients had features rarely observed in chromosomal syndromes (i.e., occipital encephalocele and tracheo-esophageal fistula). Possible reasons for such phenotypic variability are briefly discussed.

Abnormalities, Multiple↗

PubMed2005

Phenotypic variability in familial prion diseases due to the D178N mutation.

BACKGROUND: Between January 1993 and December 2003, 19 patients with familial prion diseases due to the D178N mutation were referred to the regional epidemiological registry for spongiform encephalopathies in the Basque Country in Spain, a small community of some 2,100,000 inhabitants. METHODS: Ten further patients belonging to the same pedigrees were retrospectively ascertained through neurological or neuropathological records. In four of the patients, the diagnosis was confirmed by analysing DNA obtained from paraffin blocks. In this article, we report on the clinical, genetic, and pathological features of the 23 patients carrying the D178N mutation confirmed by genetic molecular analysis. Haplotyping studies suggest a founder effect among Basque born families, explaining in part this unusually high incidence of the D178N mutation in a small community. Only two patients (8%) lack familial antecedents. RESULTS: We have observed a phenotypic variability even among homozygous 129MM patients. Our findings challenge the currently accepted belief that MM homozygosity in codon 129 is always related to a fatal familial insomnia (FFI) phenotype. Indeed, seven out of 17 patients with a 129MM genotype in this series presented with a Creutzfeldt-Jakob disease (CJD) clinicopathological picture. CONCLUSIONS: The considerable clinical and pathological overlapping observed among homozygous 129MM patients favours the view that FFI and CJD178 are the extremes of a spectrum rather than two discrete and separate entities. Other genetic or environmental factors apart from the polymorphism in codon 129 may play a role in determining the phenotypic expression of the D178N mutation in the PRNP gene.

Adult↗

PubMed1989

X-linked spastic paraplegia: evidence for homogeneity with a variable phenotype.

Hereditary spastic paraplegia (HSP) is rarely inherited in an X-linked recessive mode in pure and complicated forms. Recently, molecular linkage studies have suggested that these variant X-linked HSP conditions result from locus heterogeneity. In this paper we report on the clinical and linkage analysis of a kindred with complicated X-linked HSP. The finding in this family of a map location of the putative HSP gene in the same region as the documented for the pure HSP gene provides evidence that allelic mutations might also be responsible for the variable phenotype encountered in these X-linked disorders.

Adolescent↗