Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 6 de 6
Filter
Add more filters










Database
Language
Publication year range
1.
Hum Mol Genet ; 30(7): 575-594, 2021 05 12.
Article in English | MEDLINE | ID: mdl-33772537

ABSTRACT

The PHF6 mutation c.1024C > T; p.R342X, is a recurrent cause of Börjeson-Forssman-Lehmann Syndrome (BFLS), a neurodevelopmental disorder characterized by moderate-severe intellectual disability, truncal obesity, gynecomastia, hypogonadism, long tapering fingers and large ears (MIM#301900). Here, we generated transgenic mice with the identical substitution (R342X mice) using CRISPR technology. We show that the p.R342X mutation causes a reduction in PHF6 protein levels, in both human and mice, from nonsense-mediated decay and nonsense-associated alternative splicing, respectively. Magnetic resonance imaging studies indicated that R342X mice had a reduced brain volume on a mixed genetic background but developed hydrocephaly and a high incidence of postnatal death on a C57BL/6 background. Cortical development proceeded normally, while hippocampus and hypothalamus relative brain volumes were altered. A hypoplastic anterior pituitary was also observed that likely contributes to the small size of the R342X mice. Behavior testing demonstrated deficits in associative learning, spatial memory and an anxiolytic phenotype. Taken together, the R342X mice represent a good preclinical model of BFLS that will allow further dissection of PHF6 function and disease pathogenesis.


Subject(s)
Disease Models, Animal , Epilepsy/genetics , Face/abnormalities , Fingers/abnormalities , Genetic Predisposition to Disease/genetics , Growth Disorders/genetics , Hypogonadism/genetics , Mental Retardation, X-Linked/genetics , Mutation , Obesity/genetics , Repressor Proteins/genetics , Animals , Association Learning/physiology , Brain/diagnostic imaging , Brain/metabolism , Brain/pathology , Cells, Cultured , Epilepsy/metabolism , Epilepsy/physiopathology , Face/physiopathology , Female , Fingers/physiopathology , Gene Expression Profiling/methods , Growth Disorders/metabolism , Growth Disorders/physiopathology , Humans , Hypogonadism/metabolism , Hypogonadism/physiopathology , Magnetic Resonance Imaging/methods , Male , Mental Retardation, X-Linked/metabolism , Mental Retardation, X-Linked/physiopathology , Mice, Inbred C57BL , Mice, Transgenic , Obesity/metabolism , Obesity/physiopathology , RNA-Seq/methods , Repressor Proteins/metabolism , Spatial Memory/physiology
2.
J Med Genet ; 52(4): 269-74, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25612912

ABSTRACT

BACKGROUND: Trichothiodystrophy (TTD) is a group of rare autosomal recessive disorders that variably affect a wide range of organs derived from the neuroectoderm. The key diagnostic feature is sparse, brittle, sulfur deficient hair that has a 'tiger-tail' banding pattern under polarising light microscopy. PATIENTS AND METHODS: We describe two male cousins affected by TTD associated with microcephaly, profound intellectual disability, sparse brittle hair, aged appearance, short stature, facial dysmorphism, seizures, an immunoglobulin deficiency, multiple endocrine abnormalities, cerebellar hypoplasia and partial absence of the corpus callosum, in the absence of cellular photosensitivity and ichthyosis. Obligate female carriers showed 100% skewed X-chromosome inactivation. Linkage analysis and Sanger sequencing of 737 X-chromosome exons and whole exome sequencing was used to find the responsible gene and mutation. RESULTS: Linkage analysis localised the disease allele to a 7.75 Mb interval from Xq23-q25. We identified a nonsense mutation in the highly conserved RNF113A gene (c.901 C>T, p.Q301*). The mutation segregated with the disease in the family and was not observed in over 100,000 control X chromosomes. The mutation markedly reduced RNF113A protein expression in extracts from lymphoblastoid cell lines derived from the affected individuals. CONCLUSIONS: The association of RNF113A mutation with non-photosensitive TTD identifies a new locus for these disorders on the X chromosome. The extended phenotype within this family includes panhypopituitarism, cutis marmorata and congenital short oesophagus.


Subject(s)
Codon, Nonsense , DNA-Binding Proteins/genetics , Trichothiodystrophy Syndromes/genetics , Adolescent , Amino Acid Sequence , DNA Mutational Analysis , DNA-Binding Proteins/chemistry , Humans , Male , Molecular Sequence Data , Pedigree
3.
Nat Genet ; 40(6): 776-81, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18469813

ABSTRACT

Epilepsy and mental retardation limited to females (EFMR) is a disorder with an X-linked mode of inheritance and an unusual expression pattern. Disorders arising from mutations on the X chromosome are typically characterized by affected males and unaffected carrier females. In contrast, EFMR spares transmitting males and affects only carrier females. Aided by systematic resequencing of 737 X chromosome genes, we identified different protocadherin 19 (PCDH19) gene mutations in seven families with EFMR. Five mutations resulted in the introduction of a premature termination codon. Study of two of these demonstrated nonsense-mediated decay of PCDH19 mRNA. The two missense mutations were predicted to affect adhesiveness of PCDH19 through impaired calcium binding. PCDH19 is expressed in developing brains of human and mouse and is the first member of the cadherin superfamily to be directly implicated in epilepsy or mental retardation.


Subject(s)
Cadherins/genetics , Chromosomes, Human, X , Codon, Nonsense/genetics , Cognition Disorders/genetics , Epilepsy/genetics , Genomic Imprinting , Mutation, Missense/genetics , Animals , Brain/growth & development , Brain/metabolism , Brain/pathology , Case-Control Studies , Cognition Disorders/pathology , Epilepsy/pathology , Female , Fibroblasts/cytology , Fibroblasts/metabolism , Gene Expression Regulation, Developmental , Genes, X-Linked/genetics , Humans , In Situ Hybridization , Male , Mental Retardation, X-Linked/genetics , Mental Retardation, X-Linked/pathology , Mice/embryology , Pedigree , Phenotype , Protocadherins , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Skin/cytology , Skin/metabolism
4.
Am J Hum Genet ; 82(2): 432-43, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18252223

ABSTRACT

Submicroscopic copy-number imbalances contribute significantly to the genetic etiology of human disease. Here, we report a novel microduplication hot spot at Xp11.22 identified in six unrelated families with predominantly nonsyndromic XLMR. All duplications segregate with the disease, including the large families MRX17 and MRX31. The minimal, commonly duplicated region contains three genes: RIBC1, HSD17B10, and HUWE1. RIBC1 could be excluded on the basis of its absence of expression in the brain and because it escapes X inactivation in females. For the other genes, expression array and quantitative PCR analysis in patient cell lines compared to controls showed a significant upregulation of HSD17B10 and HUWE1 as well as several important genes in their molecular pathways. Loss-of-function mutations of HSD17B10 have previously been associated with progressive neurological disease and XLMR. The E3 ubiquitin ligase HUWE1 has been implicated in TP53-associated regulation of the neuronal cell cycle. Here, we also report segregating sequence changes of highly conserved residues in HUWE1 in three XLMR families; these changes are possibly associated with the phenotype. Our findings demonstrate that an increased gene dosage of HSD17B10, HUWE1, or both contribute to the etiology of XLMR and suggest that point mutations in HUWE1 are associated with this disease too.


Subject(s)
3-Hydroxyacyl CoA Dehydrogenases/genetics , Chromosomes, Human, X/genetics , Mental Retardation, X-Linked/genetics , Ubiquitin-Protein Ligases/genetics , Base Sequence , Blotting, Western , DNA Mutational Analysis , DNA, Complementary/genetics , Gene Dosage/genetics , Gene Duplication , Humans , In Situ Hybridization, Fluorescence , Microarray Analysis , Molecular Sequence Data , Mutation/genetics , Pedigree , Tumor Suppressor Proteins
5.
Nat Genet ; 39(9): 1127-33, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17704778

ABSTRACT

Nonsense-mediated mRNA decay (NMD) is of universal biological significance. It has emerged as an important global RNA, DNA and translation regulatory pathway. By systematically sequencing 737 genes (annotated in the Vertebrate Genome Annotation database) on the human X chromosome in 250 families with X-linked mental retardation, we identified mutations in the UPF3 regulator of nonsense transcripts homolog B (yeast) (UPF3B) leading to protein truncations in three families: two with the Lujan-Fryns phenotype and one with the FG phenotype. We also identified a missense mutation in another family with nonsyndromic mental retardation. Three mutations lead to the introduction of a premature termination codon and subsequent NMD of mutant UPF3B mRNA. Protein blot analysis using lymphoblastoid cell lines from affected individuals showed an absence of the UPF3B protein in two families. The UPF3B protein is an important component of the NMD surveillance machinery. Our results directly implicate abnormalities of NMD in human disease and suggest at least partial redundancy of NMD pathways.


Subject(s)
Mental Retardation, X-Linked/genetics , Mutation , RNA, Messenger/metabolism , RNA-Binding Proteins/genetics , Amino Acid Sequence , Cell Line, Transformed , Codon, Nonsense , DNA Mutational Analysis , Family Health , Female , Gene Expression Profiling , Humans , Immunoblotting , Male , Mental Retardation, X-Linked/pathology , Molecular Sequence Data , Pedigree , RNA Stability , RNA, Messenger/genetics , RNA-Binding Proteins/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Sequence Homology, Amino Acid , Syndrome
6.
Am J Hum Genet ; 80(2): 345-52, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17236139

ABSTRACT

We have identified three truncating, two splice-site, and three missense variants at conserved amino acids in the CUL4B gene on Xq24 in 8 of 250 families with X-linked mental retardation (XLMR). During affected subjects' adolescence, a syndrome emerged with delayed puberty, hypogonadism, relative macrocephaly, moderate short stature, central obesity, unprovoked aggressive outbursts, fine intention tremor, pes cavus, and abnormalities of the toes. This syndrome was first described by Cazebas et al., in a family that was included in our study and that carried a CUL4B missense variant. CUL4B is a ubiquitin E3 ligase subunit implicated in the regulation of several biological processes, and CUL4B is the first XLMR gene that encodes an E3 ubiquitin ligase. The relatively high frequency of CUL4B mutations in this series indicates that it is one of the most commonly mutated genes underlying XLMR and suggests that its introduction into clinical diagnostics should be a high priority.


Subject(s)
Abnormalities, Multiple/genetics , Cullin Proteins/genetics , Mental Retardation, X-Linked/genetics , Mutation , Ubiquitin-Protein Ligases/genetics , Aggression , Amino Acid Sequence , Child , Child, Preschool , Foot Deformities/genetics , Head/abnormalities , Humans , Hypogonadism/genetics , Male , Molecular Sequence Data , Obesity/genetics , Protein Subunits/genetics , Seizures/genetics , Tremor/genetics
SELECTION OF CITATIONS
SEARCH DETAIL
...