RESUMEN
STUDY DESIGN: Mutation analysis of a candidate disease gene in a cohort of patients with moderate to severe Adolescent idiopathic scoliosis (AIS). OBJECTIVE: To investigate if damaging mutations in the planar cell polarity gene VANGL1 could be identified in AIS patients. SUMMARY OF BACKGROUND DATA: AIS is a spinal deformity which occurs in 1% to 3% of the population. The cause of AIS is often unknown, but genetic factors are important in the etiology. Rare variants in genes encoding regulators of WNT/planar cell polarity (PCP) signaling were recently identified in AIS patients. METHODS: We analyzed the coding region of the VANGL1 gene for mutations using Sanger sequencing in 157 unrelated patients with moderate to severe AIS. The frequency of mutations in the patient cohort was compared with their frequency in a large cohort of controls. Functional effect of mutations were predicted in silico and analyzed in vitro by transfection of normal and mutant recombinant VANGL1 protein in Madin-Darby Canine Kidney (MDCK) cells. Cellular localization of recombinant proteins was analyzed by immunofluorescence microscopy analysis. RESULTS: In the patient cohort, we identified two rare missense mutations in VANGL1, encoding a receptor involved in WNT/PCP signaling. The mutations, p.I136N and p.F440âV, are very rare in the normal population. Both mutations are predicted to be damaging, and to affect evolutionary conserved amino acid residues of VANGL1. Functional analysis in MDCK cells showed that the mutations abolished the normal translocation of VANGL1 to the cell membrane. CONCLUSION: Our data support that mutations in genes involved in WNT/PCP signaling may be associated with AIS, but replication in other patient cohorts and further analysis of the role of WNT/PCP signaling in AIS is needed. LEVEL OF EVIDENCE: 4.
Asunto(s)
Proteínas Portadoras/genética , Polaridad Celular/genética , Proteínas de la Membrana/genética , Escoliosis/genética , Adolescente , Adulto , Anciano , Células Cultivadas , Heterocigoto , Humanos , Mutación Missense , Vía de Señalización Wnt/genéticaRESUMEN
A cis-regulatory sequence also known as zone of polarizing activity (ZPA) regulatory sequence (ZRS) located in intron 5 of LMBR1 is essential for expression of sonic hedgehog (SHH) in the developing posterior limb bud mesenchyme. Even though many point mutations causing preaxial duplication defects have been reported in ZRS, the underlying regulatory mechanism is still unknown. In this study, we analyzed the effect on transcription factor binding of a novel ZRS point mutation (463T>G) in a Pakistani family with preaxial polydactyly and triphalangeal thumb. Electrophoretical mobility shift assay demonstrated a marked difference between wild-type and the mutant probe, which uniquely bound one or several transcription factors extracted from Caco-2 cells. This finding supports a model in which ectopic anterior SHH expression in the developing limb results from abnormal binding of one or more transcription factors to the mutant sequence.
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Proteínas de la Membrana/genética , Polidactilia/genética , Elementos Reguladores de la Transcripción/genética , Pulgar/anomalías , Factores de Transcripción/metabolismo , Secuencia de Bases , Células CACO-2 , Familia , Humanos , Proteínas de la Membrana/metabolismo , Linaje , Mutación Puntual/fisiología , Polidactilia/complicaciones , Polidactilia/metabolismo , Unión Proteica , Especificidad por SustratoAsunto(s)
Proteínas Cromosómicas no Histona/genética , Aberraciones Cromosómicas , Rotura Cromosómica , Craneosinostosis/genética , Microcefalia/genética , Mutación , Proteínas del Tejido Nervioso/genética , Alelos , Animales , Proteínas de Ciclo Celular , Cromosomas/ultraestructura , Proteínas del Citoesqueleto , Análisis Mutacional de ADN , Humanos , Ratones , Repeticiones de Microsatélite/genética , FenotipoRESUMEN
Autosomal recessive primary microcephaly (MCPH) is characterized by reduced head circumference (
Asunto(s)
Microcefalia/genética , Proteínas del Tejido Nervioso/genética , Haplotipos , Heterocigoto , Humanos , Mutación , LinajeRESUMEN
Autosomal-dominant brachydactyly type A2 (BDA2), a limb malformation characterized by hypoplastic middle phalanges of the second and fifth fingers, has been shown to be due to mutations in the Bone morphogenetic protein receptor 1B (BMPR1B) or in its ligand Growth and differentiation factor 5 (GDF5). A linkage analysis performed in a mutation-negative family identified a novel locus for BDA2 on chromosome 20p12.3 that incorporates the gene for Bone morphogenetic protein 2 (BMP2). No point mutation was identified in BMP2, so a high-density array CGH analysis covering the critical interval of approximately 1.3 Mb was performed. A microduplication of approximately 5.5 kb in a noncoding sequence approximately 110 kb downstream of BMP2 was detected. Screening of other patients by qPCR revealed a similar duplication in a second family. The duplicated region contains evolutionary highly conserved sequences suggestive of a long-range regulator. By using a transgenic mouse model we can show that this sequence is able to drive expression of a X-Gal reporter construct in the limbs. The almost complete overlap with endogenous Bmp2 expression indicates that a limb-specific enhancer of Bmp2 is located within the identified duplication. Our results reveal an additional functional mechanism for the pathogenesis of BDA2, which is duplication of a regulatory element that affects the expression of BMP2 in the developing limb.
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Proteína Morfogenética Ósea 2/genética , Duplicación de Gen , Deformidades Congénitas de las Extremidades/genética , Adulto , Animales , Secuencia de Bases , Cromosomas Humanos Par 20/genética , Hibridación Genómica Comparativa , Secuencia Conservada , ADN/genética , Cartilla de ADN/genética , Femenino , Dedos/anomalías , Regulación del Desarrollo de la Expresión Génica , Humanos , Lactante , Deformidades Congénitas de las Extremidades/clasificación , Deformidades Congénitas de las Extremidades/embriología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Linaje , Fenotipo , Elementos Reguladores de la Transcripción , Secuencias Repetidas en TándemRESUMEN
Autosomal dominant inheritance is described in about 20% of all nonsyndromic hearing loss with currently 54 distinct loci (DFNA1-54), and >20 different genes identified. Seven different unconventional myosin genes are involved in ten different types of syndromic and nonsyndromic hearing loss with different patterns of inheritance: MYO7A in DFNA11/DFNB2/USH1B, MYH9 in DFNA17, MYH14 in DFNA4, MYO6 in DFNA22/DFNB37, MYO3A in DFNB30, MYO1A in DFNA48, and MYO15A in DFNB3. Two missense mutations in MYO6 (p.C442Y and p.H246R) have been characterized in families of Italian and American Caucasian extraction with autosomal dominant hearing loss, respectively, and the latter was associated with cardiomyopathy in some patients. Three Pakistani families had homozygosity for three MYO6 mutations (c.36insT, p.R1166X, and p.E216V, respectively), and was in one instance associated with retinal degeneration. In the present study, we linked autosomal dominant hearing loss in a large Danish family to a 38.9 Mb interval overlapping with the DFNA22/DFNB37 locus on chromosome 6q13. A novel nonsense mutation in MYO6 exon 25 (c.2545C > T; p.R849X) was identified in the family. The mutation co-segregated with the disease and the mutant allele is predicted to encode a truncated protein lacking the coiled-coil and globular tail domains. These domains are hypothesized to be essential for targeting myosin VI to its cellular compartments. No other system was involved indicating nonsyndromic loss. In conclusion, a novel nonsense MYO6 mutation causes post-lingual, slowly progressive autosomal dominant nonsyndromic moderate to severe hearing loss in a Danish family.
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Codón sin Sentido/genética , Familia , Pérdida Auditiva/genética , Cadenas Pesadas de Miosina/genética , Secuencia de Aminoácidos , Secuencia de Bases , Cromosomas Humanos Par 6 , Dinamarca , Genes Dominantes , Ligamiento Genético , Pérdida Auditiva/diagnóstico , Pérdida Auditiva/patología , Humanos , Datos de Secuencia Molecular , Cadenas Pesadas de Miosina/química , Linaje , Análisis de Secuencia de ADNRESUMEN
The human eye color is a quantitative trait displaying multifactorial inheritance. Several studies have shown that the OCA2 locus is the major contributor to the human eye color variation. By linkage analysis of a large Danish family, we finemapped the blue eye color locus to a 166 Kbp region within the HERC2 gene. By association analyses, we identified two SNPs within this region that were perfectly associated with the blue and brown eye colors: rs12913832 and rs1129038. Of these, rs12913832 is located 21.152 bp upstream from the OCA2 promoter in a highly conserved sequence in intron 86 of HERC2. The brown eye color allele of rs12913832 is highly conserved throughout a number of species. As shown by a Luciferase assays in cell cultures, the element significantly reduces the activity of the OCA2 promoter and electrophoretic mobility shift assays demonstrate that the two alleles bind different subsets of nuclear extracts. One single haplotype, represented by six polymorphic SNPs covering half of the 3' end of the HERC2 gene, was found in 155 blue-eyed individuals from Denmark, and in 5 and 2 blue-eyed individuals from Turkey and Jordan, respectively. Hence, our data suggest a common founder mutation in an OCA2 inhibiting regulatory element as the cause of blue eye color in humans. In addition, an LOD score of Z = 4.21 between hair color and D14S72 was obtained in the large family, indicating that RABGGTA is a candidate gene for hair color.
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Color del Ojo/genética , Efecto Fundador , Regulación de la Expresión Génica/genética , Factores de Intercambio de Guanina Nucleótido/genética , Proteínas de Transporte de Membrana/metabolismo , Mutación/genética , Secuencias Reguladoras de Ácidos Nucleicos/genética , Adulto , Alelos , Células Cultivadas , Cromosomas Humanos Par 15/genética , Dinamarca , Femenino , Ligamiento Genético , Genotipo , Factores de Intercambio de Guanina Nucleótido/metabolismo , Color del Cabello/genética , Haplotipos/genética , Humanos , Escala de Lod , Luciferasas/metabolismo , Masculino , Linaje , Polimorfismo de Nucleótido Simple/genética , Encuestas y Cuestionarios , Ubiquitina-Proteína LigasasRESUMEN
We investigated a family with a brachydactyly type A2 and identified a heterozygous arginine to glutamine (R380Q) substitution in the growth/differentiation factor 5 (GDF5) in all affected individuals. The observed mutation is located at the processing site of the protein, at which the GDF5 precursor is thought to be cleaved releasing the mature molecule from the prodomain. In order to test the effect of the mutation, we generated the GDF5-R380Q mutant and a cleavage-resistant proGDF5 mutant (R380A/R381A) in vitro. Both mutants were secreted from chicken micromass cultures, but showed diminished biological activity. Western blot analyses showed that wt GDF5 was processed by the chicken micromass cells, whereas the mutants were not, indicating that the mutations interfere with processing and that this leads to a strong reduction of biological activity. To test the requirements for GDF5 processing in vitro we produced recombinant human (rh) proGDF5 wild-type protein in Escherichia coli. The results show that unprocessed (rh) proGDF5 is virtually inactive but can be proteolytically activated by different enzymes such as trypsin, furin, and MMP3. (rh) proGDF5 could thus be used as a locally administered depot form with retarded release of activity. In contrast to mature rhGDF5, (rh) proGDF5 shows a high solubility at physiological pH, a characteristic that might be useful for therapeutic applications.
Asunto(s)
Proteínas Morfogenéticas Óseas/genética , Proteínas Morfogenéticas Óseas/metabolismo , Deformidades Congénitas de la Mano/genética , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Procesamiento Proteico-Postraduccional , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Animales , Proteínas Morfogenéticas Óseas/aislamiento & purificación , Técnicas de Cultivo de Célula , Embrión de Pollo , Pollos , Clonación Molecular , Factor 5 de Diferenciación de Crecimiento , Humanos , Datos de Secuencia Molecular , Mutación Missense , Precursores de Proteínas/aislamiento & purificación , Proteínas Recombinantes/genética , Proteínas Recombinantes/aislamiento & purificación , Proteínas Recombinantes/metabolismo , Alineación de Secuencia , SolubilidadRESUMEN
Cleft lip and/or palate (CL/P) is a common congenital malformation with a complex etiology, as many genes and environmental factors have been shown to play a role in craniofacial development. We used a genetic mapping approach to analyze a family with multiplex CL/P. A genome-wide scan with a 10 kb single nucleotide polymorphism (SNP) chip followed by fine mapping with microsatellite markers in a CL/P multiplex family suggested linkage (maximum multipoint LOD score of 2.41) to a 6.5 Mb interval at 1q32.1-q32.2. This interval was close to, but excluded IRF6. Mutations in the IRF6 (1q32.2) cause syndromic forms of CL/P, and several association studies have shown that polymorphisms in and around IRF6 are associated with non-syndromic CL/P (NSCLP). However, in the family described here, IRF6 was excluded from the linkage interval. Sequencing of selected genes in the interval and comparative genome hybridization (CGH) did not reveal any mutations or genomic aberrations. Our data suggest that an unidentified CL/P gene, or a non-coding IRF6 regulatory element in this linkage interval may have caused CL/P in this family.
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Labio Leporino/genética , Fisura del Paladar/genética , Ligamiento Genético , Factores Reguladores del Interferón/genética , Dinamarca , Salud de la Familia , Femenino , Humanos , Masculino , Linaje , Elementos Reguladores de la TranscripciónRESUMEN
The ADULT syndrome (Acro-Dermato-Ungual-Lacrimal-Tooth, OMIM 103285) is a rare ectodermal dysplasia associated with limb malformations and caused by heterozygous mutations in p63. ADULT syndrome has clinical overlap with other p63 mutation syndromes, such as EEC (OMIM 604292), LMS (OMIM 603543), AEC (106260), RHS (129400) and SHFM4 (605289). ADULT syndrome characteristics are ectrodactyly, ectodermal dysplasia, mammary gland hypoplasia and normal lip and palate. The latter findings allow differentiation from EEC syndrome. LMS differs by milder ectodermal involvement. Here, we report three new unrelated ADULT syndrome families, all with mutations of arginine 298. On basis of 16 patients in five families with R298 mutation, we delineate the ADULT syndrome phenotype. In addition, we have documented a gain-of-function effect on the dNp63gamma isoform caused by this mutation. We discuss the possible relevance of oral squamous cell carcinoma in one patient, who carries this p63 germline mutation.
Asunto(s)
Anomalías Múltiples/genética , Arginina , Displasia Ectodérmica/genética , Genes Supresores de Tumor , Activación Transcripcional , Adulto , Niño , Femenino , Humanos , Deformidades Congénitas de las Extremidades/genética , Masculino , Persona de Mediana Edad , Mutación Missense , Fenotipo , Síndrome , Anomalías Dentarias/genéticaRESUMEN
To further explore the allelic heterogeneity within the group of LEMD3-related disorders, we have screened a larger series of patients including 5 probands with osteopoikilosis or Buschke-Ollendorff syndrome (BOS), 2 families with the co-occurrence of melorheostosis and BOS, and 12 unrelated patients with isolated melorheostosis. Seven novel LEMD3 mutations were identified, all predicted to result in loss-of-function of the protein. We confirm that loss-of-function mutations in the LEMD3 gene can result in either osteopoikilosis or BOS. However, LEMD3 germline mutations were only found in two melorheostosis patients belonging to a different BOS family and one sporadic patient with melorheostosis. The additional presence of osteopoikilosis lesions in these patients seemed to distinguish them from the group of sporadic melorheostosis patients where no germline LEMD3 mutation was identified. Somatic mosaicism for a LEMD3 mutation in the latter group was also not observed, and therefore we must conclude that the genetic defect in the majority of sporadic and isolated melorheostosis remains unknown.
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Enfermedades del Desarrollo Óseo/genética , Melorreostosis/genética , Proteínas de la Membrana/genética , Mutación , Proteínas Nucleares/genética , Osteopoiquilosis/genética , Alelos , Proteínas de Unión al ADN , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Mosaicismo , Linaje , SíndromeRESUMEN
A phenotype-genotype correlation was previously described for carriers of different sized of polyalanine expansions in HOXD13. We report on a detailed comparison of 55 members (approximately 220 limbs) from 4 Danish families with duplications of 21 or 27 bp, expanding the polyalanine repeat from 15 to 22 and 24 residues, respectively. Two of these were previously described by Danish pioneers of human genetics, Tage Kemp and Oluf Thomsen. A clinical score was assigned to each limb based on manifestations assumed to represent different degrees of a duplication defect in hand rays 3-4 and foot rays 4-5. The length of metacarpals and phalangeal bones in rays 1, 2, and 5 was measured on hand radiographs and converted to Z-scores. The relative difference between corresponding right and left bones and directional, total, and fluctuating asymmetry was calculated for each individual. All of these parameters were compared between carriers of the +9 alanine expansion, the +7 alanine expansion, and non-mutation carriers with affected parents from the two families. Upper limb scores and the rate of abnormal bones (>2SD) were significantly higher in the first group than in the others. The first metacarpal and the middle phalanx of the little finger were significantly shorter, and the proximal phalanx of the index finger was significantly longer in this group than in the others. An increased level of total and fluctuating asymmetry was observed in long expansion carriers. Thus, our data have added evidence to the phenotype-genotype correlation previously reported, which was further extended to include lesser involvement of bones in ray 1, 2, and 5.
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Proteínas de Homeodominio/genética , Péptidos/genética , Factores de Transcripción/genética , Secuencia de Bases , Cartilla de ADN , Dinamarca , Femenino , Genotipo , Humanos , Masculino , Linaje , FenotipoRESUMEN
We report on a father and a son with nasal and limb defects characteristic of Laurin-Sandrow syndrome (LSS) excluding for the first time X-linked inheritance in this rare condition. Based on a search for genes expressed late during nose formation and early in limb formation we identified retinoic acid receptor B (RARB) and retinoic acid receptor G (RARG) as possible candidate genes and sequenced bidirectionally including all exons and intron-exon bounders. We identified a single nucleotide substitution in intron 2 of RARB, which is conserved in human, chimp, dog, mouse, rat, and chicken. However, it was located 83 bp from exon 2, suggesting it is a rare polymorphism which does not account for the phenotype. No other mutations were found. This suggests that another yet unknown gene is responsible for the condition.
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Anomalías Múltiples/patología , Deformidades Congénitas del Pie/patología , Deformidades Congénitas de la Mano/patología , Nariz/anomalías , Anomalías Múltiples/genética , Adulto , Niño , Predisposición Genética a la Enfermedad/genética , Humanos , Patrón de Herencia , Masculino , Receptores de Ácido Retinoico/genética , Factores Sexuales , SíndromeRESUMEN
Here we describe 2 mutations in growth and differentiation factor 5 (GDF5) that alter receptor-binding affinities. They cause brachydactyly type A2 (L441P) and symphalangism (R438L), conditions previously associated with mutations in the GDF5 receptor bone morphogenetic protein receptor type 1b (BMPR1B) and the BMP antagonist NOGGIN, respectively. We expressed the mutant proteins in limb bud micromass culture and treated ATDC5 and C2C12 cells with recombinant GDF5. Our results indicated that the L441P mutant is almost inactive. The R438L mutant, in contrast, showed increased biological activity when compared with WT GDF5. Biosensor interaction analyses revealed loss of binding to BMPR1A and BMPR1B ectodomains for the L441P mutant, whereas the R438L mutant showed normal binding to BMPR1B but increased binding to BMPR1A, the receptor normally activated by BMP2. The binding to NOGGIN was normal for both mutants. Thus, the brachydactyly type A2 phenotype (L441P) is caused by inhibition of the ligand-receptor interaction, whereas the symphalangism phenotype (R438L) is caused by a loss of receptor-binding specificity, resulting in a gain of function by the acquisition of BMP2-like properties. The presented experiments have identified some of the main determinants of GDF5 receptor-binding specificity in vivo and open new prospects for generating antagonists and superagonists of GDF5.
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Receptores de Proteínas Morfogenéticas Óseas de Tipo 1 , Proteínas Morfogenéticas Óseas , Dedos/patología , Deformidades Congénitas de las Extremidades/genética , Mutación Puntual , Secuencia de Aminoácidos , Animales , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/genética , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/metabolismo , Proteínas Morfogenéticas Óseas/química , Proteínas Morfogenéticas Óseas/genética , Proteínas Morfogenéticas Óseas/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Diferenciación Celular , Línea Celular , Estructuras Embrionarias/anatomía & histología , Estructuras Embrionarias/patología , Estructuras Embrionarias/fisiología , Dedos/diagnóstico por imagen , Factor 5 de Diferenciación de Crecimiento , Humanos , Hibridación in Situ , Deformidades Congénitas de las Extremidades/patología , Ratones , Datos de Secuencia Molecular , Fenotipo , Unión Proteica , Conformación Proteica , Radiografía , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Alineación de Secuencia , Técnicas de Cultivo de TejidosRESUMEN
In 1988 Pfeiffer and Kapferer reported on a patient with sensorineural deafness, psychomotor delay, hypospadias, cerebral manifestations, and bilateral synostosis of the 4th and 5th metacarpals and metatarsals. Synostosis of the 4th and 5th metacarpals and metatarsals is a very rare defect that has been described as an isolated Mendelian defect, as part of multiple congenital anomaly (MCA) patterns, and in different syndromes. Among a total of 2,023,155 liveborn infants in the Spanish Collaborative Study of Congenital Malformations (ECEMC), we observed only two cases with this type of metacarpal fusion, for a frequency of 1/1,011,577. One had the isolated defect, and the other one that we are describing here, had an MCA pattern similar to that described by Pfeiffer and Kapferer [1988]. We tested HOXD13 but did not find any mutations in exons and intron-exon boundaries. To our knowledge this case is the second one reported with this syndrome.
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Anomalías Múltiples/patología , Genitales Femeninos/anomalías , Pérdida Auditiva Sensorineural/patología , Discapacidad Intelectual/patología , Sinostosis/patología , Anomalías Múltiples/genética , Preescolar , Análisis Mutacional de ADN , Femenino , Proteínas de Homeodominio/genética , Humanos , Lactante , Metacarpo/anomalías , Huesos Metatarsianos/anomalías , Mutación , Síndrome , Factores de Transcripción/genéticaRESUMEN
Warburg Micro syndrome (WARBM1) is a severe autosomal recessive disorder characterized by developmental abnormalities of the eye and central nervous system and by microgenitalia. We identified homozygous inactivating mutations in RAB3GAP, encoding RAB3 GTPase activating protein, a key regulator of the Rab3 pathway implicated in exocytic release of neurotransmitters and hormones, in 12 families with Micro syndrome. We hypothesize that the underlying pathogenesis of Micro syndrome is a failure of exocytic release of ocular and neurodevelopmental trophic factors.
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Mutación , Proteínas de Unión al GTP rab/metabolismo , Dominio Catalítico , Sistema Nervioso Central/anomalías , Anomalías del Ojo/patología , Genitales/anomalías , Humanos , Datos de Secuencia Molecular , Síndrome , Proteínas de Unión al GTP rab/genéticaRESUMEN
The aim of this study was to investigate the expression of the p63 gene in normal human tooth buds at different gestational stages. This is the first detailed study of p63 expression in normal human prenatal tooth primordia. The material consisted of sections of the midaxial tissue block from the cranial base of three human fetuses of gestational ages (GA) 11, 15, and 21 weeks. The sections included tooth primordia representing cap stages and bell stages of human tooth morphogenesis. In the present study, immunostaining was carried out using the primary antibody, monoclonal mouse anti human p63 protein, clone 4A4. The sections were counterstained with hematoxylin Mayer. p63 immunoreactivity was identified by microscopy. The study showed a positive reaction of p63 in both the cap stage and the bell stage. In both stages, positivity was observed in the cells of the oral mucosa, the inner and outer enamel epithelium, and in the primary and secondary dental lamina. In the early cap stage, there is a strong positive reaction to p63 in the enamel knot, but not in the late cap stage. We suggest that p63 may have an important regulatory function in the enamel knot.
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Esmalte Dental/embriología , Expresión Génica/genética , Odontogénesis/genética , Fosfoproteínas/genética , Germen Dentario/embriología , Transactivadores/genética , Proteínas de Unión al ADN , Genes Supresores de Tumor , Edad Gestacional , Humanos , Fosfoproteínas/metabolismo , Germen Dentario/metabolismo , Transactivadores/metabolismo , Factores de Transcripción , Proteínas Supresoras de TumorRESUMEN
Oculo-dento-digital dysplasia (ODDD) [OMIM 164200] is a rare autosomal dominant pleiotropic disorder comprising ocular, craniofacial, and digital anomalies, caused by mutations in the gap junction alpha-1 gene (GJA1 or Connexin 43 (CX43)) [Paznekas et al., 2003]. In a Danish family affected over five generations, we found a novel mutation, 286G --> A, resulting in Val96Met. We provide an easy method for mutation detection by use of the restriction enzyme Nde1 and discuss possible pathogenetic mechanisms, arguing that loss of function cannot be excluded. This is the second article reporting ODDD mutations.