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1.
Int J Epidemiol ; 40(5): 1146-54, 2011 Oct.
Article in English | MEDLINE | ID: mdl-22039189

ABSTRACT

An earlier preliminary paper is expanded. Women who had given birth to one or more infants with a neural tube defect were recruited into a trial of periconceptional vitamin supplementation. Two hundred mothers attending five centres were fully supplemented (FS), 50 were partially supplemented (PS), and 300 were unsupplemented (US). Neural tube defect recurrences in the study pregnancies were 1(0.5%), in FS, none in PS, and 13 (4%) in US mothers. The difference in outcome between FS and US mothers is significant. The most likely explanation is that supplementation has prevented some neural tube defects, but further studies are needed.


Subject(s)
Neural Tube Defects/history , Preconception Care/history , Vitamins/history , Female , History, 20th Century , Humans , Neural Tube Defects/prevention & control , Pregnancy , Vitamins/therapeutic use
2.
Adv Otorhinolaryngol ; 65: 75-85, 2007.
Article in English | MEDLINE | ID: mdl-17245027

ABSTRACT

Otosclerosis is one of the commonest causes of hearing loss in adults. The hereditary nature of the disease has been acknowledged for over a century but the precise genetic basis of the disorder has as yet not been characterised. It is currently recognised that familial otosclerosis exhibits autosomal dominant inheritance with variable penetrance and expression. More recently, family linkage studies have identified three chromosomal regions that can be ascribed to this disorder: otosclerosis 1 on chromosome 15, otosclerosis 2 on chromosome 7 and a third locus on chromosome 6. The genes responsible for the disease within these regions remain to be defined. The work presented in this paper firstly examined the familial nature of the disease in a cohort of individuals that had undergone surgery for otosclerosis. Following detailed ascertainment, pedigrees were constructed for subsequent genetic analysis. The laboratory analysis included linkage analysis of the candidate region on the long arm of chromosome 15, linkage analysis of the aggrecan protein gene within the 15q region and linkage analysis to chromosome 7q. The pedigree studies confirmed the hereditary nature of otosclerosis and the recognised mode of inheritance. Linkage to the chromosome 15 locus, the candidate aggrecan gene and the chromosome 7 locus was excluded, confirming that otosclerosis exhibits locus heterogeneity.


Subject(s)
Chromosome Mapping , Otosclerosis/genetics , Adult , Aggrecans/genetics , Chromosome Aberrations , Chromosomes, Human, Pair 15 , Chromosomes, Human, Pair 7 , Chromosomes, Human, Pair 8 , Genes, Recessive , Humans , Oligonucleotide Probes , Pedigree , Retrospective Studies
3.
Br J Dermatol ; 151(6): 1261-5, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15606524

ABSTRACT

The co-occurrence of two rare recessive genetic conditions in apparently unrelated individuals or families is extremely rare. Two geographically distant and apparently unrelated families were identified in which individuals were simultaneously affected by two rare recessive mendelian syndromes, Papillon-Lefevre syndrome and type 1 oculocutaneous albinism. The families were tested for mutations in the causative genes, cathepsin C (CTSC) and tyrosinase (TYR), respectively, by direct sequencing. To assess the relationship of the two families, both families were tested for polymorphisms at eight microsatellite markers spanning both CTSC and TYR loci. Independent mutations (c.318-1G-->A and c.817G-->C/p.W272C) were identified in CTSC and TYR, respectively, that were shared by the affected individuals in both families. The two affected genes lie close together on chromosome bands 11q14.2-14.3, and studies with linked genetic markers suggested that the families shared a small chromosomal segment carrying both mutations that had been transmitted intact from a remote common ancestor. The co-occurrence of the two rare diseases in multiple families depends on their shared chromosomal location, but not on any shared pathogenic mechanism.


Subject(s)
Albinism, Oculocutaneous/genetics , Papillon-Lefevre Disease/genetics , Rare Diseases/genetics , Adult , Albinism, Oculocutaneous/complications , Base Sequence , Cathepsin C/genetics , Child , DNA Mutational Analysis , Female , Genes, Recessive , Genetic Markers , Haplotypes , Humans , Male , Monophenol Monooxygenase/genetics , Mutation , Papillon-Lefevre Disease/complications , Pedigree , Rare Diseases/complications
4.
Eur J Hum Genet ; 11(6): 468-74, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12774041

ABSTRACT

Pax genes are a highly conserved family of developmental control genes that encode transcription factors. In vertebrates, Pax genes play a role in pattern formation during embryogenesis. Mutations in Pax genes have been associated with both spontaneous mouse mutants and congenital human diseases. The mouse Pax1 mutant phenotype undulated is characterised by vertebral segmentation defects reminiscent of the human disorder Klippel-Feil syndrome (KFS). To determine whether PAX1 haploinsufficiency plays a role in KFS, we have defined the gene structure of the human PAX1 gene and screened 63 KFS patients for mutations in this gene. Differences in the PAX1 sequence were detected in eight patients. Two patients had a silent change within the paired box that was also seen in 2/303 control chromosomes. The other variants were missense, silent or intronic changes not represented in the control panel tested. The significance of these results and the possible role of PAX1 in the pathogenesis of KFS are discussed.


Subject(s)
DNA-Binding Proteins/genetics , Genetic Testing , Klippel-Feil Syndrome/genetics , Transcription Factors/genetics , Base Sequence , DNA Mutational Analysis , DNA Primers , Humans , Molecular Sequence Data , Paired Box Transcription Factors , Polymorphism, Genetic
8.
Eur J Hum Genet ; 8(12): 955-63, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11175284

ABSTRACT

Supravalvular aortic stenosis (SVAS) is a congenital narrowing of the ascending aorta which can occur sporadically, as an autosomal dominant condition, or as one component of Williams syndrome. SVAS is caused by translocations, gross deletions and point mutations that disrupt the elastin gene (ELN) on 7q11.23. Functional hemizygosity for elastin is known to be the cause of SVAS in patients with gross chromosomal abnormalities involving ELN. However, the pathogenic mechanisms of point mutations are less clear. One hundred patients with diagnosed SVAS and normal karyotypes were screened for mutations in the elastin gene to further elucidate the molecular pathology of the disorder. Mutations associated with the vascular disease were detected in 35 patients, and included nonsense, frameshift, translation initiation and splice site mutations. The four missense mutations identified are the first of this type to be associated with SVAS. Here we describe the spectrum of mutations occurring in familial and sporadic SVAS and attempt to define the mutational mechanisms involved in SVAS. SVAS shows variable penetrance within families but the progressive nature of the disorder in some cases, makes identification of the molecular lesions important for future preventative treatments.


Subject(s)
Aortic Stenosis, Supravalvular/genetics , Elastin/genetics , Alternative Splicing , Codon, Initiator , Codon, Nonsense , DNA/analysis , Female , Humans , Male , Mutation, Missense , Pedigree , Polymorphism, Genetic
9.
Eur J Pediatr ; 159 Suppl 3: S232-5, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11216906

ABSTRACT

UNLABELLED: Hereditary deafness is highly heterogeneous genetically, with over 100 loci so far identified. Routine diagnostic mutation screening can be done only when a candidate gene has been identified, and preferably a candidate mutation. For syndromic forms of hearing loss it is often possible to predict the gene involved. Non-syndromic loss is much more intractable to diagnostic mutation screening because of the extensive locus heterogeneity. However, mutations in the connexin 26 (GJB2) gene and the mitochondrial m. 1555A > G mutation are sufficiently frequent in some populations to justify mutation testing. Identifying the genes mutated in syndromic hearing loss can help delineate developmental pathways. CONCLUSION: The example of Waardenburg syndrome is used to illustrate how unravelling developmental pathways can be more complicated than defining metabolic pathways through biochemical defects. Developmental genes tend to be organised into networks rather than linear pathways, and transcription factors act in a combinatorial manner. This makes developmental pathways harder to unravel genetically than metabolic pathways.


Subject(s)
Deafness/genetics , Connexin 26 , Connexins/genetics , Deafness/diagnosis , Humans , Melanocytes/physiology , Mitochondria/genetics , Waardenburg Syndrome/genetics
10.
Nat Genet ; 23(4): 421-4, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10581027

ABSTRACT

Papillon-Lefèvre syndrome, or keratosis palmoplantaris with periodontopathia (PLS, MIM 245000), is an autosomal recessive disorder that is mainly ascertained by dentists because of the severe periodontitis that afflicts patients. Both the deciduous and permanent dentitions are affected, resulting in premature tooth loss. Palmoplantar keratosis, varying from mild psoriasiform scaly skin to overt hyperkeratosis, typically develops within the first three years of life. Keratosis also affects other sites such as elbows and knees. Most PLS patients display both periodontitis and hyperkeratosis. Some patients have only palmoplantar keratosis or periodontitis, and in rare individuals the periodontitis is mild and of late onset. The PLS locus has been mapped to chromosome 11q14-q21 (refs 7, 8, 9). Using homozygosity mapping in eight small consanguineous families, we have narrowed the candidate region to a 1.2-cM interval between D11S4082 and D11S931. The gene (CTSC) encoding the lysosomal protease cathepsin C (or dipeptidyl aminopeptidase I) lies within this interval. We defined the genomic structure of CTSC and found mutations in all eight families. In two of these families we used a functional assay to demonstrate an almost total loss of cathepsin C activity in PLS patients and reduced activity in obligate carriers.


Subject(s)
Aggressive Periodontitis/enzymology , Aggressive Periodontitis/genetics , Cathepsin C/deficiency , Cathepsin C/genetics , Papillon-Lefevre Disease/enzymology , Papillon-Lefevre Disease/genetics , Point Mutation , Aggressive Periodontitis/pathology , Base Sequence , Chromosomes, Human, Pair 11/genetics , DNA Primers/genetics , DNA, Complementary/genetics , Exons , Female , Genes, Recessive , Genetic Linkage , Humans , Introns , Male , Microsatellite Repeats , Papillon-Lefevre Disease/pathology , Pedigree
11.
Eur J Hum Genet ; 7(7): 737-47, 1999.
Article in English | MEDLINE | ID: mdl-10573005

ABSTRACT

Williams-Beuren syndrome (WS) is a developmental disorder caused by a hemizygous microdeletion of approximately 1.4MB at chromosomal location 7q11.23. The transcription map of the WS critical region is not yet complete. We have isolated and characterised a 3.4 kb gene, GTF3, which occupies about 140 kb of the deleted region. Northern blot analysis showed that the gene is expressed in skeletal muscle and heart, and RT-PCR analysis showed expression in a range of adult tissues with stronger expression in foetal tissues. Part of the conceptual GTF3 protein sequence is almost identical to a recently reported slow muscle-fibre enhancer binding protein MusTRD1, and shows significant homology to the 90 amino-acid putative helix-loop-helix repeat (HLH) domains of the transcription factor TFII-I (encoded for by the gene GTF2I). These genes may be members of a new family of transcription factors containing this HLH-like repeated motif. Both GTF3 and GTF2I map within the WS deleted region, with GTF2I being positioned distal to GTF3. GTF3 is deleted in patients with classic WS, but not in patients we have studied with partial deletions of the WS critical region who have only supravalvular aortic stenosis. A feature of WS is abnormal muscle fatiguability, and we suggest that haploinsufficiency of the GTF3 gene may be the cause of this.


Subject(s)
Gene Deletion , Gene Expression , Muscle Proteins , Muscle, Skeletal/metabolism , Nuclear Proteins , Trans-Activators , Transcription Factors/genetics , Williams Syndrome/genetics , Amino Acid Sequence , Base Sequence , Blotting, Northern , DNA, Complementary/genetics , DNA-Binding Proteins/genetics , Gene Expression Profiling , Gene Library , Helix-Loop-Helix Motifs , Humans , In Situ Hybridization, Fluorescence , Molecular Sequence Data , Reverse Transcriptase Polymerase Chain Reaction , Sequence Homology, Amino Acid , Transcription Factors/metabolism , Williams Syndrome/metabolism
12.
Hum Mol Genet ; 8(9): 1785-9, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10441344

ABSTRACT

The Yemenite deaf-blind hypopigmentation syndrome was first observed in a Yemenite sister and brother showing cutaneous hypopigmented and hyperpigmented spots and patches, microcornea, coloboma and severe hearing loss. A second case, observed in a girl with similar skin symptoms and hearing loss but without microcornea or coloboma, was reported as a mild form of this syndrome. Here we show that a SOX10 missense mutation is responsible for the mild form, resulting in a loss of DNA binding of this transcription factor. In contrast, no SOX10 alteration could be found in the other, severe case of the Yemenite deaf-blind hypopigmentation syndrome. Based on genetic, clinical, molecular and functional data, we suggest that these two cases represent two different syndromes. Moreover, as mutations of the SOX10 transcription factor were previously described in Waardenburg-Hirschsprung disease, these results show that SOX10 mutations cause various types of neurocristopathy.


Subject(s)
DNA-Binding Proteins/genetics , High Mobility Group Proteins/genetics , Hypopigmentation/genetics , Amino Acid Sequence , Cells, Cultured , Craniofacial Abnormalities/genetics , DNA Mutational Analysis , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/metabolism , High Mobility Group Proteins/chemistry , Host Cell Factor C1 , Humans , Models, Molecular , Molecular Sequence Data , Nuclear Proteins/analysis , Octamer Transcription Factor-1 , Polymorphism, Single-Stranded Conformational , Protein Binding/genetics , Protein Structure, Tertiary , SOXE Transcription Factors , Syndrome , Transcription Factors/genetics , Transcription Factors/metabolism , Yemen
13.
Genomics ; 58(2): 138-45, 1999 Jun 01.
Article in English | MEDLINE | ID: mdl-10366445

ABSTRACT

Williams syndrome (WS) is a contiguous gene syndrome caused by hemizygosity for a chromosomal deletion at 7q11.23. The range of phenotypes includes mental retardation, dysmorphic facies, heart abnormalities, short stature, a specific cognitive profile, hyperacusis, and infantile hypercalcaemia. To identify all the deleted genes, we have constructed a detailed physical map and complete BAC/PAC contig of the critical region, extending a distance of approximately 2 Mb and delimited by the nondeleted markers D7S1816 and D7S489A. Somatic cell hybrids of WS patients were made and used to define the centromeric and telomeric deletion breakpoints, enabling the size of the WS deletion to be defined as approximately 1.4 Mb. Genes previously mapped to the region have been located on the contig, and we have isolated eight transcripts, two of which have been characterized as the genes CPETR1 and CPETR2. This contig and expressed sequence map will form the basis for the construction of a complete transcription map of the deleted region and will enable genotype-phenotype correlations to be attempted to identify the individual components of WS.


Subject(s)
Chromosome Mapping , Physical Chromosome Mapping , Williams Syndrome/genetics , Chromosomes, Artificial, Yeast , Chromosomes, Human, Pair 7 , DNA Primers , Humans , Hybrid Cells , In Situ Hybridization, Fluorescence
14.
J Bone Miner Res ; 14(5): 730-9, 1999 May.
Article in English | MEDLINE | ID: mdl-10320521

ABSTRACT

Pseudovitamin D-defiency rickets (PDDR) is an autosomal recessive disorder characterized by hypocalcemia, rickets (which are resistant to treatment with vitamin D), and low or undetectable serum levels of 1,25-dihydroxyvitamin D (1,25(OH)2D). The symptoms are corrected with 1,25(OH)2D treatment, and the disease is now believed to result from a defect in the cytochrome P450 component (P450c1; CYP27B1) of the renal 25-hydroxyvitamin D-1alpha-hydroxylase (1-OHase). We have studied genomic DNA from three families with PDDR and have identified the same homozygous mutation in the P450c1 gene in two of the index cases, causing a frameshift in exon 8, resulting in a premature stop codon in the heme-binding domain. The two cases in the third kindred were compound heterozygotes with missense mutations in exons 6 and 9. We have also identified a C/T polymorphism in intron 6 of the P450c1 genomic DNA. Interferon gamma-inducible 1-OHase activity in blood-derived macrophages was shown by 1,25(OH)2D synthesis in all control cells tested (37-184 fmol/h/106 cells) and those from the PDDR family parents (34-116 fmol/h/106 cells) but was totally absent from the patients' cells, indicating a defect in their macrophage 1-OHase, similar to the presumed renal defect. The assumption of similarity between the renal and macrophage P450c1 was supported by our ability to clone a 514 bp sequence, including the heme-binding region of the macrophage P450c1 cDNA from controls, which was identical to that published for both the renal and keratinocyte P450c1 cDNAs.


Subject(s)
Chromosomes, Human, Pair 12 , Cytochrome P-450 Enzyme System/genetics , Macrophages/enzymology , Mutation , Rickets/genetics , Steroid Hydroxylases/genetics , 24,25-Dihydroxyvitamin D 3/metabolism , 25-Hydroxyvitamin D3 1-alpha-Hydroxylase/genetics , Base Sequence , Cells, Cultured , Child , Child, Preschool , Cholestanetriol 26-Monooxygenase , Cloning, Molecular , DNA/chemistry , DNA/metabolism , Female , Ferredoxins/metabolism , Heme/metabolism , Humans , Infant , Introns , Male , Molecular Sequence Data , Pedigree , Polymorphism, Genetic , Rickets/enzymology
15.
Genes Chromosomes Cancer ; 25(1): 16-25, 1999 May.
Article in English | MEDLINE | ID: mdl-10221335

ABSTRACT

Loss of CDKN2A expression was demonstrated by immunohistochemistry in 87% of oral and oropharyngeal squamous cell carcinoma (OSCC) primary tumor samples. By contrast, DNA studies showed a much lower frequency of loss of the CDKN2A gene. Point mutations and promoter methylation of CDKN2A were seen in 7% and 23%, respectively, of primary tumors. Loss of heterozygosity analysis using a dense set of 9p markers showed allelic imbalance that included CDKN2A in only 31% of samples, but a further 47% showed loss at loci near CDKN2A with apparent retention of CDKN2A. No tumor with any allelic imbalance expressed CDKN2A, whether or not the imbalance appeared to involve the CDKN2A locus. We interpret these data as showing partially overlapping deletions on the two 9p homologues, with homozygous deletion of CDKN2A masked by amplification of contaminating stromal material. Our data show that inactivation of the CDKN2A gene products is a near-universal step in the development of oral and oropharyngeal squamous cell carcinomas, and we suggest that homozygous deletion is the most common mechanism of inactivation. The CDKN2A locus may be particularly prone to deletion because it encodes two unrelated tumor suppressor proteins, CDKN2A (p16INK4a) and p19ARF, and deletion, but not point mutation or methylation, would inactivate both gene products. However, our results also suggest that complex patterns of allelic imbalance in primary squamous carcinomas in general may not provide reliable evidence for the existence of multiple tumor suppressor genes within a single chromosomal region.


Subject(s)
Carcinoma, Squamous Cell/genetics , DNA, Neoplasm/analysis , Genes, p16/genetics , Genes, p16/physiology , Mouth Neoplasms/genetics , Oropharyngeal Neoplasms/genetics , 5' Untranslated Regions/genetics , Chromosomes, Human, Pair 9/genetics , CpG Islands/genetics , DNA Methylation , DNA Mutational Analysis , Gene Expression Regulation, Neoplastic/genetics , Gene Expression Regulation, Neoplastic/physiology , Humans , Loss of Heterozygosity
16.
Am J Hum Genet ; 64(1): 118-25, 1999 Jan.
Article in English | MEDLINE | ID: mdl-9915950

ABSTRACT

In Williams syndrome (WS), a deletion of approximately 1.5 Mb on one copy of chromosome 7 causes specific physical, cognitive, and behavioral abnormalities. Molecular dissection of the phenotype may be a route to identification of genes important in human cognition and behavior. Among the genes known to be deleted in WS are ELN (which encodes elastin), LIMK1 (which encodes a protein tyrosine kinase expressed in the developing brain), STX1A (which encodes a component of the synaptic apparatus), and FZD3. Study of patients with deletions or mutations confined to ELN showed that hemizygosity for elastin is responsible for the cardiological features of WS. LIMK1 and STX1A are good candidates for cognitive or behavioral aspects of WS. Here we describe genetic and psychometric testing of patients who have small deletions within the WS critical region. Our results suggest that neither LIMK1 hemizygosity (contrary to a previous report) nor STX1A hemizygosity is likely to contribute to any part of the WS phenotype, and they emphasize the importance of such patients for dissecting subtle but highly penetrant phenotypes.


Subject(s)
Chromosomes, Human, Pair 7 , Intelligence/genetics , Receptors, G-Protein-Coupled , Williams Syndrome/genetics , Adult , Antigens, Surface/genetics , Child , Chromosome Mapping , DNA-Binding Proteins/genetics , Elastin/genetics , Female , Frizzled Receptors , Humans , In Situ Hybridization, Fluorescence , Lim Kinases , Male , Middle Aged , Nerve Tissue Proteins/genetics , Phenotype , Polymerase Chain Reaction , Protein Kinases , Protein Serine-Threonine Kinases/genetics , Receptors, Cell Surface/genetics , Sequence Deletion , Spatial Behavior , Syntaxin 1 , Visual Perception , Williams Syndrome/physiopathology , Zinc Fingers/genetics
17.
J Med Genet ; 35(12): 973-7, 1998 Dec.
Article in English | MEDLINE | ID: mdl-9863591

ABSTRACT

Patients who present with unilateral vestibular schwannomas either at a young age or with additional features of type 2 neurofibromatosis (NF2) are at risk of developing bilateral disease and transmitting a risk of neurogenic tumours to their offspring. We have identified 15 patients from a series of 537 with unilateral vestibular schwannomas who also had one or more of the following: other tumours (10/15), features of NF2 (3/15), or a family history of neurogenic tumours (5/15). No germline NF2 mutations were detected and in 7/9 cases where tumour material was available for analysis a germline mutation in the NF2 gene has been excluded. Although a possibility of gonosomal mosaicism still exists, exclusion tests for the offspring are now possible. We suggest a general strategy, based on analysis of tumour DNA, for distinguishing sporadic and familial cases of tumours caused by two hit mechanisms. Application of this strategy suggests that most instances of unilateral vestibular schwannoma which do not fulfil criteria for NF2 represent chance occurrences.


Subject(s)
Membrane Proteins/genetics , Neurilemmoma/diagnosis , Neurofibromatosis 2/diagnosis , Adult , Aged , Diagnosis, Differential , Female , Humans , Male , Middle Aged , Neurilemmoma/genetics , Neurofibromatosis 2/genetics , Neurofibromin 2
18.
Hum Genet ; 102(5): 499-506, 1998 May.
Article in English | MEDLINE | ID: mdl-9654197

ABSTRACT

Waardenburg syndrome (WS) type 1 is an autosomal dominant disorder characterized by sensorineural hearing loss, pigmentary abnormalities of the eye, hair, and skin, and dystopia canthorum. The phenotype is variable and affected individuals may exhibit only one or a combination of several of the associated features. To assess the relationship between phenotype and gene defect, clinical and genotype data on 48 families (271 WS individuals) collected by members of the Waardenburg Consortium were pooled. Forty-two unique mutations in the PAX3 gene, previously identified in these families, were grouped in five mutation categories: amino acid (AA) substitution in the paired domain, AA substitution in the homeodomain, deletion of the Ser-Thr-Pro-rich region, deletion of the homeodomain and the Ser-Thr-Pro-rich region, and deletion of the entire gene. These mutation classes are based on the structure of the PAX3 gene and were chosen to group mutations predicted to have similar defects in the gene product. Association between mutation class and the presence of hearing loss, eye pigment abnormality, skin hypopigmentation, or white forelock was evaluated using generalized estimating equations, which allowed for incorporation of a correlation structure that accounts for potential similarity among members of the same family. Odds for the presence of eye pigment abnormality, white forelock, and skin hypopigmentation were 2, 8, and 5 times greater, respectively, for individuals with deletions of the homeodomain and the Pro-Ser-Thr-rich region compared to individuals with an AA substitution in the homeodomain. Odds ratios that differ significantly from 1.0 for these traits may indicate that the gene products resulting from different classes of mutations act differently in the expression of WS. Although a suggestive association was detected for hearing loss with an odds ratio of 2.6 for AA substitution in the paired domain compared with AA substitution in the homeodomain, this odds ratio did not differ significantly from 1.0.


Subject(s)
DNA-Binding Proteins/genetics , Mutation , Transcription Factors , Waardenburg Syndrome/genetics , Genotype , Hearing Disorders/genetics , Humans , Odds Ratio , PAX3 Transcription Factor , Paired Box Transcription Factors , Phenotype , Pigmentation Disorders/genetics , Waardenburg Syndrome/diagnosis
19.
Hum Mol Genet ; 7(6): 1021-8, 1998 Jun.
Article in English | MEDLINE | ID: mdl-9580666

ABSTRACT

Elastin is the protein responsible for the characteristic elastic properties of many tissues including the skin, lungs and large blood vessels. Loss-of-function mutations in the elastin gene are known to cause the heart defect supravalvular aortic stenosis (SVAS). We and others have identified deletions, nonsense mutations and splice site mutations in SVAS patients that abolish the function of one elastin gene. We have now identified an elastin mutation in a patient with a completely different phenotype, the rare autosomal dominant condition cutis laxa. A frameshift mutation in exon 32 of the elastin gene is predicted to replace 37 amino acids at the C-terminus of elastin by a novel sequence of 62 amino acids. mRNA and immunoprecipitation studies show that the mutant allele is expressed. Electron microscopy of skin sections shows abnormal branching and fragmentation in the amorphous elastin component, and immunocytochemistry shows reduced elastin deposition in the elastic fibres and fewer microfibrils in the dermis. These findings suggest that the mutant tropoelastin protein is synthesized, secreted and incorporated into the elastic matrix, where it alters the architecture of elastic fibres. Interference with cross-linking would reduce elastic recoil in affected tissues and explain the cutis laxa phenotype.


Subject(s)
Cutis Laxa/genetics , Elastic Tissue/ultrastructure , Elastin/genetics , Frameshift Mutation , Tropoelastin/genetics , Adult , Amino Acid Sequence , Base Sequence , Cutis Laxa/pathology , DNA , DNA Mutational Analysis , Elasticity , Female , Gene Expression , Genes, Dominant , Humans , Molecular Sequence Data , Protein Conformation , Skin/ultrastructure , Tropoelastin/biosynthesis , Tropoelastin/chemistry , Tropoelastin/metabolism
20.
Clin Dysmorphol ; 7(1): 17-20, 1998 Jan.
Article in English | MEDLINE | ID: mdl-9546825

ABSTRACT

A mother and her son with albinism and sensorineural deafness compatible with Tietz syndrome (MIM 103500) are reported. An in-frame deletion of the MITF gene that is identical at the molecular level to the mouse mi mutant allele has been found in this family. MITF gene mutations account for 20% of Waardenburg syndrome (WS) type II. These data, together with the wide spectrum of mutant alleles reported in mi mice (which have pigmentary disorders), suggest that MITF could be regarded as a candidate gene in various pigmentation disorders in man.


Subject(s)
Albinism/complications , Albinism/genetics , DNA-Binding Proteins/genetics , Deafness/complications , Deafness/genetics , Sequence Deletion , Transcription Factors , Adult , Alleles , Animals , Deafness/congenital , Female , Humans , Infant , Male , Mice , Mice, Mutant Strains , Microphthalmia-Associated Transcription Factor , Phenotype , Pigmentation Disorders/genetics , Syndrome , Waardenburg Syndrome/classification , Waardenburg Syndrome/genetics
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