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Compound Heterozygous Mutations (compound + heterozygous_mutation)

Distribution by Scientific Domains

Medical Sciences	68%
Life Sciences	31%

Distribution within Medical Sciences

Neurology	45%
Dermatology	17%

Selected Abstracts

Compound Heterozygous Mutations in the Vitamin D Receptor in a Patient With Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets With Alopecia,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 4 2009
Yulin Zhou
Abstract Hereditary vitamin D-resistant rickets (HVDRR) is a rare recessive genetic disorder caused by mutations in the vitamin D receptor (VDR). In this study, we examined the VDR in a young girl with clinical features of HVDRR including rickets, hypophosphatemia, and elevated serum 1,25(OH)2D. The girl also had total alopecia. Two mutations were found in the VDR gene: a nonsense mutation (R30X) in the DNA-binding domain and a unique 3-bp in-frame deletion in exon 6 that deleted the codon for lysine at amino acid 246 (,K246). The child and her mother were both heterozygous for the 3-bp deletion, whereas the child and her father were both heterozygous for the R30X mutation. Fibroblasts from the patient were unresponsive to 1,25(OH)2D3 as shown by their failure to induce CYP24A1 gene expression, a marker of 1,25(OH)2D3 responsiveness. [3H]1,25(OH)2D3 binding and immunoblot analysis showed that the patient's cells expressed the VDR,K246 mutant protein; however, the amount of VDR,K246 mutant protein was significantly reduced compared with wildtype controls. In transactivation assays, the recreated VDR,K246 mutant was unresponsive to 1,25(OH)2D3. The ,K246 mutation abolished heterodimerization of the mutant VDR with RXR, and binding to the coactivators DRIP205 and SRC-1. However, the ,K246 mutation did not affect the interaction of the mutant VDR with the corepressor Hairless (HR). In summary, we describe a patient with compound heterozygous mutations in the VDR that results in HVDRR with alopecia. The R30X mutation truncates the VDR, whereas the ,K246 mutation prevents heterodimerization with RXR and disrupts coactivator interactions. [source]

Compound heterozygous mutations in the , -glutamyl carboxylase gene cause combined deficiency of all vitamin K-dependent blood coagulation factors

BRITISH JOURNAL OF HAEMATOLOGY, Issue 4 2004
Simone Rost
Summary Hereditary combined deficiency of the vitamin K-dependent coagulation factors II, VII, IX, X, protein C, S and protein Z (VKCFD) is a very rare autosomal recessive inherited bleeding disorder. The phenotype may result from functional deficiency of either the , -glutamyl carboxylase (GGCX) or the vitamin K epoxide reductase (VKOR) complex. We report on the third case of VKCFD1 with mutations in the , -glutamyl carboxylase gene, which is remarkable because of compound heterozygosity. Two mutations were identified: a splice site mutation of exon 3 and a point mutation in exon 11, resulting in the replacement of arginine 485 by proline. Screening of 100 unrelated normal chromosomes by restriction fragment length polymorphism and denaturing high-performance liquid chromatography analysis excluded either mutation as a frequent polymorphism. Substitution of vitamin K could only partially normalize the levels of coagulation factors. It is suggested that the missense mutation affects either the propeptide binding site or the vitamin K binding site of GGCX. [source]

A novel compound heterozygous mutation in the F13A gene causing hereditary factor XIII deficiency in a Chinese family

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 1 2006
S. WU
No abstract is available for this article. [source]

Epidemiological Approach to Identifying Genetic Predispositions for Atypical Hemolytic Uremic Syndrome

ANNALS OF HUMAN GENETICS, Issue 1 2010
Maren Sullivan
Summary Atypical hemolytic uremic syndrome (aHUS) is caused by several susceptibility genes. A registry including analyses of susceptibility genes, familial occurrence and genotype-phenotype correlation should provide classification insights. Registry data of 187 unrelated index patients included age at onset, gender, family history, relapse of aHUS and potentially triggering conditions. Mutation analyses were performed in the genes CFH, CD46 and CFI and in the six potential susceptibility genes, FHR1 to FHR5 and C4BP. Germline mutations were identified in 17% of the index cases; 12% in CFH, 3% in CD46 and 2% in CFI. Twenty-nine patients had heterozygous mutations and one each had a homozygous and compound heterozygous mutation. Mutations were not found in the genes FHR1-5 and C4BP. In 40% of the patients with familial HUS a mutation was found. Penetrance by age 45 was 50% among carriers of any mutation including results of relatives of mutation-positive index cases. The only risk factor for a mutation was family history of HUS (p = 0.02). Penetrance of aHUS in carriers of mutations is not complete. Occurrence of homo- and heterozygous mutations in the same gene suggests that the number of necessary DNA variants remains unclear. Among clinical information only familial occurrence predicts a mutation. [source]

Ataxia with vitamin E deficiency in southeast Norway, case report

ACTA NEUROLOGICA SCANDINAVICA, Issue 2009
J. Koht
Background,, Ataxia with vitamin E deficiency (AVED) is a rare cause of hereditary ataxia in north European countries with unknown prevalence. Few cases are reported from these countries. Methods ,Through a systematic population based study of hereditary ataxia in southeast Norway subjects were classified and investigated. Aims , To report a subject with ataxia due to vitamin E deficiency in Norway. Results , One patient with AVED was identified. The subject was a 45 years old woman with progressive ataxia from preschool age. When she was 12 years old Friedreich's ataxia was diagnosed after neurological examination. At the age of 45 re-evaluation and re-examination was performed and genetic analysis of the Frataxin gene was negative. At that time she had truncal and extremities ataxia, titubation of the head, pes cavus, inverted plantar response, loss of proprioceptive and vibration sense and a severe sensory neuropathy. Vitamin E in serum was undetectable and genetic analysis detected a compound heterozygous mutation, p.A120T and p.R134X, in the ,-tocopherol transport protein gene on chromosome 8q13. Discussion , Vitamin E should always be assessed in progressive ataxia of genetic or unexplained causes and especially with a Friedreich's ataxia-like phenotype since treatment is available. Conclusion,, AVED is rare in Norway, but exists, and we here report the first genetically confirmed subject with ataxia due to vitamin E deficiency in Norway. [source]

Cerebral palsy in siblings caused by compound heterozygous mutations in the gene encoding protein C

DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 5 2010
CHOONG YI FONG
We report two sisters with extensive bilateral periventricular haemorrhagic infarction (PVHI) causing cerebral palsy (CP). The older sister presented at 20 months with cortical visual blindness, spastic diplegia, and purpura fulminans. The younger sister presented aged 3 days old with apnoeas and multifocal seizures. She subsequently had global developmental delay, cortical visual blindness, spastic quadriplegia, epilepsy, and purpura fulminans at age 2 years. Neuroimaging of both siblings showed bilateral PVHI consistent with bilateral cerebral intramedullary venous thrombosis occurring at under 28 weeks' gestation for the older sister and around time of birth for the younger sister. At latest follow-up, the older sister (13y) has spastic diplegia at Gross Motor Function Classification System (GMFCS) level II, and the younger sister (10y) has spastic quadriplegia at GMFCS level IV. Both sisters showed partial quantitative reduction in plasma protein C antigen and severe qualitative reduction in plasma protein C anticoagulant activity. They were heterozygous for two independent mutations in the protein C gene (PROC). There was no other risk factor for CP. To our knowledge, this is the first family reported with compound heterozygous PROC mutations as the likely genetic cause of familial CP. This report adds to the list of known monogenic causes of CP. [source]

A unique case of limb-girdle muscular dystrophy type 2A carrying novel compound heterozygous mutations in the human CAPN3 gene

EUROPEAN JOURNAL OF NEUROLOGY, Issue 7 2007
E. Matsubara
A unique sib pair afflicted by limb girdle muscular dystrophy type 2A (LGMD2A) is described showing a slowly progressive autosomal recessive type of muscular dystrophy with onset in the third and fourth decades. The patients had early asymmetric muscle involvement characterized by prominent biceps brachii atrophy with sparing of the knee extensors. Additional findings included elevation of serum creatine kinase level, myopathic EMG changes and dystrophic type of pathology on muscle biopsy. Asymmetrical wasting of muscles in the extremities exhibited uniform and highly selective CT imaging patterns. RNA and DNA analyses confirmed novel compound heterozygous mutations (R147X/L212F) in the human CAPN3 gene. [source]

Low frequency of Parkin, Tyrosine Hydroxylase, and GTP Cyclohydrolase I gene mutations in a Danish population of early-onset Parkinson's Disease

EUROPEAN JOURNAL OF NEUROLOGY, Issue 4 2006
J. M. Hertz
Autosomal recessive Parkinson's disease (PD) with early-onset may be caused by mutations in the parkin gene (PARK2). We have ascertained 87 Danish patients with an early-onset form of PD (age at onset ,40 years, or ,50 years if family history is positive) in a multicenter study in order to determine the frequency of PARK2 mutations. Analysis of the GTP cyclohydrolase I gene (GCH1) and the tyrosine hydroxylase gene (TH), mutated in dopa-responsive dystonia and juvenile PD, have also been included. Ten different PARK2 mutations were identified in 10 patients. Two of the patients (2.3%) were found to have homozygous or compound heterozygous mutations, and eight of the patients (9.2%) were found to be heterozygous. A mutation has been identified in 10.4% of the sporadic cases and in 15.0% of cases with a positive family history of PD. One patient was found to be heterozygous for both a PARK2 mutation and a missense mutation (A6T) in TH of unknown significance. It cannot be excluded that both mutations contribute to the phenotype. No other putative disease causing TH or GCH1 mutations were found. In conclusion, homozygous, or compound heterozygous PARK2 mutations, and mutations in GCH1 and TH, are rare even in a population of PD patients with early-onset of the disease. [source]

The human orthologue of murine Mpzl3 with predicted adhesive and immune functions is a potential candidate gene for immune-related hereditary hair loss

EXPERIMENTAL DERMATOLOGY, Issue 3 2009
Peter Racz
Abstract:, We have recently reported a mutation within the conserved immunoglobulin V-type domain of the predicted adhesion protein Mpzl3 (MIM 611707) in rough coat (rc) mice with severe skin abnormalities and progressive cyclic hair loss. In this study, we tested the hypothesis that the human orthologue MPZL3 on chromosome 11q23.3 is a candidate for similar symptoms in humans. The predicted conserved MPZL3 protein has two transmembrane motifs flanking an extracellular Ig-like domain. The R100Q rc mutation is within the Ig-domain recognition loop that has roles in T-cell receptors and cell adhesion. Results of the rc mouse study, 3D structure predictions, homology with Myelin Protein Zero and EVA1, comprehensive database analyses of polymorphisms and mutations within the human MPZL3 gene and its cell, tissue expression and immunostaining pattern indicate that homozygous or compound heterozygous mutations of MPZL3 might be involved in immune-mediated human hereditary disorders with hair loss. [source]

Syndrome-causing mutations of the BLM gene in persons in the Bloom's Syndrome Registry,,

HUMAN MUTATION, Issue 8 2007
James German
Abstract Bloom syndrome (BS) is caused by homozygous or compound heterozygous mutations in the RecQ DNA helicase gene BLM. Since the molecular isolation of BLM, characterization of BS-causing mutations has been carried out systematically using samples stored in the Bloom's Syndrome Registry. In a survey of 134 persons with BS from the Registry, 64 different mutations were identified in 125 of them, 54 that cause premature protein-translation termination and 10 missense mutations. In 102 of the 125 persons in whom at least one BLM mutation was identified, the mutation was recurrent, that is, it was shared by two or more persons with BS; 19 of the 64 different mutations were recurrent. Ethnic affiliations of the persons who carry recurrent mutations indicate that the majority of such persons inherit their BLM mutation identical-by-descent from a recent common ancestor, a founder. The presence of widespread founder mutations in persons with BS points to population genetic processes that repeatedly and pervasively generate mutations that recur in unrelated persons. Hum Mutat 28(8), 743,753, 2007. Published 2007 Wiley-Liss, Inc. [source]

Compound Heterozygous Mutations in the Vitamin D Receptor in a Patient With Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets With Alopecia,

Netherton syndrome in two Japanese siblings with a novel mutation in the SPINK5 gene: immunohistochemical studies of LEKTI and other epidermal molecules

BRITISH JOURNAL OF DERMATOLOGY, Issue 5 2005
Y. Shimomura
Summary Background, Netherton syndrome (NS) is a severe autosomal recessive disorder characterized by ichthyosiform erythroderma, bamboo hair and atopy. The disease is caused by mutations in the SPINK5 gene, which encodes a putative serine protease inhibitor, LEKTI (lymphoepithelial Kazal-type-related inhibitor). Previous studies have clearly shown a crucial role for LEKTI in skin barrier formation. Objectives, To identify pathogenic mutations in two Japanese siblings with NS, and further to investigate the consequences of the mutations at the protein level. Methods, To screen for mutations in the SPINK5 gene, all of its exons and splice junctions were amplified by polymerase chain reaction and directly sequenced. In addition, immunohistochemical staining of LEKTI, desmoglein (Dsg) 1 and elafin was performed with their specific antibodies. Results, Mutation analysis resulted in the identification of compound heterozygous mutations, Q713X and R790X, in the SPINK5 gene of both patients. The former one is a novel mutation. Immunohistochemical studies in one patient demonstrated a complete absence of LEKTI and a strong expression of elafin in the patient's skin. Dsg1 was normally expressed in our patient. Conclusions, In this report, we describe compound heterozygous mutations in the SPINK5 gene in two Japanese siblings with NS. The result of immunohistochemistry shows LEKTI deficiency and upregulation of elafin in the skin of one patient. Furthermore, our data indicate that degradation of Dsg1 does not always occur in NS. [source]

Constitutive deficiency in DNA mismatch repair

CLINICAL GENETICS, Issue 6 2007
KEA Felton
Mutations in the DNA mismatch repair (MMR) genes are associated with the inheritance of hereditary non-polyposis colorectal cancer, also known as Lynch syndrome, a cancer syndrome with an average age at onset of 44. Individuals presenting with colorectal cancer are diagnosed with Lynch I, whereas individuals who present with extra-colonic tumors (such as endometrial, stomach, etc.) are identified as patients with Lynch syndrome II. Recently, 30 families have been reported with inheritance of biallelic mutations in the MMR genes. Here we summarize the phenotype of individuals with inheritance of homozygous or compound heterozygous mutations in the MMR genes that result in a complete lack of protein or greatly compromised protein function. In contrast to individuals with Lynch syndrome I and II, individuals with no MMR function present with childhood onset of hematological and brain malignancies, whereas residual MMR function can also result in gastrointestinal cancers and an age of onset in the second to fourth decade. Individuals with biallelic MMR mutations often present with café-au-lait spots, regardless of the level of MMR function remaining. Thus, the inheritance of two MMR gene mutations is a separate entity from Lynch I or II or the subtypes Turcot and Muir,Torre. [source]

Constitutive deficiency in DNA mismatch repair: is it time for Lynch III?

CLINICAL GENETICS, Issue 6 2007
KEA Felton
Hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome types I and II, and the related subtypes Turcot and Muir,Torre syndrome, have all been associated with inheritance of germ line mutations in the DNA mismatch repair (MMR) genes. Fifty individuals have recently been identified with an early onset of a different spectrum of cancers associated with inheritance of two MMR mutations , resulting either in a constitutive loss of MMR function, or greatly impaired MMR function. In contrast to Lynch I and II individuals, individuals with inheritance of homozygous or compound heterozygous mutations in the MMR genes that result in a complete lack of protein, present with hematological and brain malignancies in the first decade of life. Biallelic mutations with compromised but residual protein function present with a broader spectrum of cancers (brain, hematological or gastrointestinal) in the second to fourth decades of life. We propose that inheritance of two MMR mutations in an individual and the unique tumor spectrum that occurs with an early onset should be defined separately from Lynch syndrome I and II, or the subtypes Turcot and Muir,Torre. We suggest Lynch III as an appropriate name for identifying individuals with constitutively compromised MMR associated with biallelic mutations. [source]

PINK1 heterozygous rare variants: prevalence, significance and phenotypic spectrum,,

HUMAN MUTATION, Issue 4 2008
Roberta Marongiu
Abstract Heterozygous rare variants in the PINK1 gene, as well as in other genes causing autosomal recessive parkinsonism, have been reported both in patients and healthy controls. Their pathogenic significance is uncertain, but they have been suggested to represent risk factors to develop Parkinson disease (PD). The few large studies that assessed the frequency of PINK1 heterozygotes in cases and controls yielded controversial results, and the phenotypic spectrum is largely unknown. We retrospectively analyzed the occurrence of PINK1 heterozygous rare variants in over 1100 sporadic and familial patients of all onset ages and in 400 controls. Twenty patients and 6 controls were heterozygous, with frequencies (1.8% vs. 1.5%) not significantly different in the two groups. Clinical features of heterozygotes were indistinguishable to those of wild-type patients, with mean disease onset 10 years later than in carriers of two mutations but worse disease progression. A meta-analysis indicated that, in PINK1 heterozygotes, the PD risk is only slightly increased with a non significant odds ratio of 1.62. These findings suggest that PINK1 heterozygous rare variants play only a minor susceptibility role in the context of a multifactorial model of PD. Hence, their significance should be kept distinct from that of homozygous/compound heterozygous mutations, that cause parkinsonism inherited in a mendelian fashion. © 2008 Wiley-Liss, Inc. [source]