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1.
Biomolecules ; 14(9)2024 Aug 26.
Artículo en Inglés | MEDLINE | ID: mdl-39334831

RESUMEN

Desbuquois dysplasia type 1 (DBQD1) is a recessive chondrodysplasia caused by mutations in the CANT1 gene, encoding for the Golgi Calcium-Activated Nucleotidase 1 (CANT1). The enzyme hydrolyzes UDP, the by-product of glycosyltransferase reactions, but it might play other roles in different cell types. Using a Cant1 knock-out mouse, we demonstrated that CANT1 is crucial for glycosaminoglycan (GAG) synthesis; however, its impact on the biochemical properties of cartilage proteoglycans remains unknown. Thus, in this work, we characterized decorin and aggrecan from primary chondrocyte cultures and cartilage biopsies of mutant mice at post-natal day 4 by Western blots and further investigated their distribution in the cartilage extracellular matrix (ECM) by immunohistochemistry. We demonstrated that the GAG synthesis defect caused by CANT1 impairment led to the synthesis and secretion of proteoglycans with shorter GAG chains compared with wild-type animals. However, this alteration did not result in the synthesis and secretion of decorin and aggrecan in the unglycanated form. Interestingly, the defect was not cartilage-specific since also skin decorin showed a reduced hydrodynamic size. Finally, immunohistochemical studies in epiphyseal sections of mutant mice demonstrated that the proteoglycan structural defect moderately affected decorin distribution in the ECM.


Asunto(s)
Agrecanos , Decorina , Modelos Animales de Enfermedad , Animales , Decorina/metabolismo , Decorina/genética , Agrecanos/metabolismo , Agrecanos/genética , Ratones , Ratones Noqueados , Cartílago/metabolismo , Cartílago/patología , Condrocitos/metabolismo , Nucleotidasas/metabolismo , Nucleotidasas/genética , Proteoglicanos/metabolismo , Proteoglicanos/genética , Polidactilia/metabolismo , Polidactilia/genética , Polidactilia/patología , Glicosaminoglicanos/metabolismo , Enanismo/metabolismo , Enanismo/genética , Enanismo/patología , Anomalías Craneofaciales/metabolismo , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/patología , Matriz Extracelular/metabolismo , Inestabilidad de la Articulación/metabolismo , Inestabilidad de la Articulación/patología , Inestabilidad de la Articulación/genética , Células Cultivadas , Osificación Heterotópica
2.
Mol Genet Genomic Med ; 12(6): e2468, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38864382

RESUMEN

BACKGROUND: Polydactyly, particularly of the index finger, remains an intriguing anomaly for which no specific gene or locus has been definitively linked to this phenotype. In this study, we conducted an investigation of a three-generation family displaying index finger polydactyly. METHODS: Exome sequencing was conducted on the patient, with a filtration to identify potential causal variation. Validation of the obtained variant was conducted by Sanger sequencing, encompassing all family members. RESULTS: Exome analysis uncovered a novel heterozygous missense variant (c.1482A>T; p.Gln494His) at the zinc finger DNA-binding domain of the GLI3 protein within the proband and all affected family members. Remarkably, the variant was absent in unaffected individuals within the pedigree, underscoring its association with the polydactyly phenotype. Computational analyses revealed that GLI3 p.Gln494His impacts a residue that is highly conserved across species. CONCLUSION: The GLI3 zinc finger DNA-binding region is an essential part of the Sonic hedgehog signaling pathway, orchestrating crucial aspects of embryonic development through the regulation of target gene expression. This novel finding not only contributes valuable insights into the molecular pathways governing polydactyly during embryonic development but also has the potential to enhance diagnostic and screening capabilities for this condition in clinical settings.


Asunto(s)
Mutación Missense , Proteínas del Tejido Nervioso , Linaje , Polidactilia , Proteína Gli3 con Dedos de Zinc , Femenino , Humanos , Masculino , Dedos/anomalías , Heterocigoto , Factores de Transcripción de Tipo Kruppel/genética , Proteínas del Tejido Nervioso/genética , Polidactilia/genética , Polidactilia/patología , Pueblos del Sudeste Asiático , Proteína Gli3 con Dedos de Zinc/genética , Proteína Gli3 con Dedos de Zinc/metabolismo , Dedos de Zinc/genética
3.
Eur Rev Med Pharmacol Sci ; 28(8): 3216-3226, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38708480

RESUMEN

OBJECTIVE: The study aims to provide guidance on the identification of multiple-digit malformations as potential biomarkers and therapeutic targets. MATERIALS AND METHODS: Single-cell RNA sequencing (scRNA-seq) data of four multiple-finger malformation samples were downloaded from the GEO public database. Fibroblasts and keratinocytes were divided into cellular subpopulations and the transcription factors of different subpopulations were analyzed. The regulatory network of transcription factors and their target genes were constructed to analyze the functionality of regulons. RESULTS: Examination of the transcriptional profile data from 11,806 single cells uncovered significant associations between regulons and cell function in polydactyly. Specifically, the analysis highlighted the involvement of HOX family members and GLI2 transcription factors, including HOXD13, MSX2, LHX2, EMX2, LEF1, CREB3L2, and LHX2, in the polydactyly process within fibroblast cells. Furthermore, it sheds light on the roles of HES2 and GLIS1 in the formation and development of keratinocytes. CONCLUSIONS: Significant presence of transcription factors, especially HOXD13, MSX2, and LHX2, may be strongly related to the development of polydactyly.


Asunto(s)
Polidactilia , Factores de Transcripción , Humanos , Fibroblastos/metabolismo , Queratinocitos/metabolismo , Polidactilia/genética , Polidactilia/patología , Polidactilia/metabolismo , Análisis de Expresión Génica de una Sola Célula , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transcriptoma
4.
Am J Med Genet A ; 194(7): e63566, 2024 07.
Artículo en Inglés | MEDLINE | ID: mdl-38357848

RESUMEN

PRKACA-related, atrial defects-polydactyly-multiple congenital malformation syndrome is a recently described skeletal ciliopathy, which is caused by disease-causing variants in PRKACA. The primary phenotypic description includes atrial septal defects, and limb anomalies including polydactyly and short limbs. To date, only four molecularly proven patients have been reported in the literature with a recurrent variant, c.409G>A p.Gly137Arg in PRKACA. In this study, we report the fifth affected individual with the same variant and review the clinical features and radiographic findings of this rare syndrome.


Asunto(s)
Anomalías Múltiples , Polidactilia , Humanos , Polidactilia/genética , Polidactilia/patología , Polidactilia/diagnóstico , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Anomalías Múltiples/diagnóstico , Femenino , Defectos del Tabique Interatrial/genética , Defectos del Tabique Interatrial/diagnóstico por imagen , Defectos del Tabique Interatrial/diagnóstico , Defectos del Tabique Interatrial/patología , Masculino , Fenotipo , Mutación/genética , Cardiopatías Congénitas/genética , Cardiopatías Congénitas/patología , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/diagnóstico por imagen , India
5.
Nature ; 626(7997): 151-159, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38233525

RESUMEN

Enhancers control the location and timing of gene expression and contain the majority of variants associated with disease1-3. The ZRS is arguably the most well-studied vertebrate enhancer and mediates the expression of Shh in the developing limb4. Thirty-one human single-nucleotide variants (SNVs) within the ZRS are associated with polydactyly4-6. However, how this enhancer encodes tissue-specific activity, and the mechanisms by which SNVs alter the number of digits, are poorly understood. Here we show that the ETS sites within the ZRS are low affinity, and identify a functional ETS site, ETS-A, with extremely low affinity. Two human SNVs and a synthetic variant optimize the binding affinity of ETS-A subtly from 15% to around 25% relative to the strongest ETS binding sequence, and cause polydactyly with the same penetrance and severity. A greater increase in affinity results in phenotypes that are more penetrant and more severe. Affinity-optimizing SNVs in other ETS sites in the ZRS, as well as in ETS, interferon regulatory factor (IRF), HOX and activator protein 1 (AP-1) sites within a wide variety of enhancers, cause gain-of-function gene expression. The prevalence of binding sites with suboptimal affinity in enhancers creates a vulnerability in genomes whereby SNVs that optimize affinity, even slightly, can be pathogenic. Searching for affinity-optimizing SNVs in genomes could provide a mechanistic approach to identify causal variants that underlie enhanceropathies.


Asunto(s)
Elementos de Facilitación Genéticos , Extremidades , Polidactilia , Proteínas Proto-Oncogénicas c-ets , Humanos , Elementos de Facilitación Genéticos/genética , Extremidades/embriología , Extremidades/patología , Mutación con Ganancia de Función , Proteínas de Homeodominio/metabolismo , Factores Reguladores del Interferón/metabolismo , Especificidad de Órganos/genética , Penetrancia , Fenotipo , Polidactilia/embriología , Polidactilia/genética , Polidactilia/patología , Polimorfismo de Nucleótido Simple , Unión Proteica , Proteínas Proto-Oncogénicas c-ets/metabolismo , Factor de Transcripción AP-1/metabolismo
6.
Anim Genet ; 55(2): 277-281, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38282540

RESUMEN

Polydactyly is a genetic abnormality that affects both pig welfare and industry profits. Despite efforts to explore the genetic basis of pig polydactyly, progress remains limited. In this study, we analyzed a group of Large White pigs with postaxial polydactyly, including 29 cases and 79 controls from 24 families. High-depth sequencing was performed on 20 pigs, while low-depth sequencing was improved through imputation for the remaining pigs. A genome-wide association study (GWAS) and genetic differentiation were conducted using the resequencing dataset, resulting in the identification of 48 significantly associated SNPs and 27 candidate regions. The genetic differentiation regions on chromosomes 5 and 18, which harbored GWAS-identified SNPs, were delineated as confidence regions. The confidence region at Chr18: 1.850-1.925 Mb covers the fifth intron of LMBR1, a gene that contains an important regulatory element for SHH, known as ZRS. Mutations in this ZRS have been found to cause polydactyly in animals and humans. Therefore, we propose LMBR1 as a prospective candidate gene for postaxial polydactyly. These findings emphasize the importance of exploring the role of ZRS within LMBR1 in the pathogenesis of polydactyly in pigs.


Asunto(s)
Dedos/anomalías , Polidactilia , Enfermedades de los Porcinos , Dedos del Pie/anomalías , Humanos , Animales , Porcinos/genética , Estudio de Asociación del Genoma Completo/veterinaria , Polidactilia/genética , Polidactilia/veterinaria , Polidactilia/patología , Dedos/patología , Mutación , Enfermedades de los Porcinos/genética
7.
Genes (Basel) ; 14(4)2023 04 05.
Artículo en Inglés | MEDLINE | ID: mdl-37107627

RESUMEN

Polydactyly is a rare autosomal dominant or recessive appendicular patterning defect of the hands and feet, phenotypically characterized by the duplication of digits. Postaxial polydactyly (PAP) is the most common form and includes two main types: PAP type A (PAPA) and PAP type B (PAPB). Type A involves a well-established extra digit articulated with the fifth or sixth metacarpal, while type B presents a rudimentary or poorly developed superfluous digit. Pathogenic variants in several genes have been identified in isolated and syndromic forms of polydactyly. The current study presents two Pakistani families with autosomal recessive PAPA with intra- and inter-familial phenotype variability. Whole-exome sequencing and Sanger analysis revealed a novel missense variant in KIAA0825 (c.3572C>T: p.Pro1191Leu) in family A and a known nonsense variant in GLI1 (c.337C>T: p.Arg113*) in family B. In silico studies of mutant KIAA0825 and GLI1 proteins revealed considerable structural and interactional modifications that suggest an abnormal function of the proteins leading to the disease phenotype. The present study broadens the mutational spectrum of KIAA0825 and demonstrates the second case of a previously identified GLI1 variant with variable phenotypes. These findings facilitate genetic counseling in Pakistani families with a polydactyly-related phenotype.


Asunto(s)
Polidactilia , Humanos , Proteína con Dedos de Zinc GLI1/genética , Polidactilia/genética , Polidactilia/patología , Dedos , Mutación
8.
Am J Med Genet A ; 191(1): 100-107, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36308343

RESUMEN

We present a large, ten-generation family of 273 individuals with 84 people having preaxial polydactyly/triphalangeal thumb due to a pathogenic variant in the zone of polarizing activity regulatory sequence (ZRS) within the exon 5 of LMBR1. The causative change maps to position 396 of the ZRS, located at position c.423 + 4909C > T (chr7:156791480; hg38; LMBR1 ENST00000353442.10; rs606231153 NG_009240.2) in the intron 5 of LMBR1. The first affected individual with the disorder was traced back to mid-1700, when some settlers and workers established in Cervera de Buitrago, a small village about 82 km North to Madrid. Clinical and radiological studies of most of the affected members have been performed for 42 years (follow-up of the family by LFGA). Molecular studies have confirmed a pathogenic variant in the ZRS that segregates in this family. To the best of our knowledge, this is the largest family with preaxial polydactyly/triphalangeal thumb reported so far.


Asunto(s)
Proteínas de la Membrana , Polidactilia , Humanos , Proteínas de la Membrana/genética , Linaje , Polidactilia/genética , Polidactilia/patología , Pulgar/patología
9.
Am J Med Genet A ; 188(6): 1826-1830, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35170189

RESUMEN

Primary cilia are a component of almost all vertebrate cells with a crucial role in sensing and transducing environmental signals during tissue development. Their dysfunction is known as ciliopathies and can manifest with a wide spectrum of clinical disorders. Overlapping features and molecular heterogeneity of ciliopathies make diagnoses distinctly challenging. In this group of diseases, tectonic genes, and their mutations play an important role. We present a first-trimester fetus with occipital encephalocele and OFD type IV caused by TCTN3 compound heterozygous pathogenic variants: c.1423_1429del (p.Arg475Serfs*10) and c.3G>A (initiator codon). A severe arm anomaly was described in our case, with two fingers along the atrophic forearm and polydactyly on other limbs. This could be a new phenotypic characteristic contributing to further understanding of TCTN3-related disorders as well as other tectonic proteins in ciliopathy spectrum diseases.


Asunto(s)
Ciliopatías , Polidactilia , Ciliopatías/genética , Encefalocele/diagnóstico por imagen , Encefalocele/genética , Feto/anomalías , Humanos , Mutación , Polidactilia/patología
10.
PLoS Genet ; 17(12): e1009982, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34928956

RESUMEN

Sonic Hedgehog/GLI3 signaling is critical in regulating digit number, such that Gli3-deficiency results in polydactyly and Shh-deficiency leads to digit number reductions. SHH/GLI3 signaling regulates cell cycle factors controlling mesenchymal cell proliferation, while simultaneously regulating Grem1 to coordinate BMP-induced chondrogenesis. SHH/GLI3 signaling also coordinates the expression of additional genes, however their importance in digit formation remain unknown. Utilizing genetic and molecular approaches, we identified HES1 as a downstream modifier of the SHH/GLI signaling axis capable of inducing preaxial polydactyly (PPD), required for Gli3-deficient PPD, and capable of overcoming digit number constraints of Shh-deficiency. Our data indicate that HES1, a direct SHH/GLI signaling target, induces mesenchymal cell proliferation via suppression of Cdkn1b, while inhibiting chondrogenic genes and the anterior autopod boundary regulator, Pax9. These findings establish HES1 as a critical downstream effector of SHH/GLI3 signaling in the development of PPD.


Asunto(s)
Proteínas Hedgehog/genética , Proteínas del Tejido Nervioso/genética , Factor de Transcripción PAX9/genética , Polidactilia/genética , Pulgar/anomalías , Factor de Transcripción HES-1/genética , Proteína Gli3 con Dedos de Zinc/genética , Animales , División Celular/genética , Proliferación Celular/genética , Condrogénesis/genética , Cromatina/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Modelos Animales de Enfermedad , Humanos , Esbozos de los Miembros/crecimiento & desarrollo , Esbozos de los Miembros/metabolismo , Mesodermo/crecimiento & desarrollo , Ratones , Polidactilia/patología , Pulgar/patología
11.
Int J Mol Sci ; 22(17)2021 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-34502207

RESUMEN

The complexity of skeletal pathologies makes use of in vivo models essential to elucidate the pathogenesis of the diseases; nevertheless, chondrocyte and osteoblast cell lines provide relevant information on the underlying disease mechanisms. Due to the limitations of primary chondrocytes, immortalized cells represent a unique tool to overcome this problem since they grow very easily for several passages. However, in the immortalization procedure the cells might lose the original phenotype; thus, these cell lines should be deeply characterized before their use. We immortalized primary chondrocytes from a Cant1 knock-out mouse, an animal model of Desbuquois dysplasia type 1, with a plasmid expressing the SV40 large and small T antigen. This cell line, based on morphological and biochemical parameters, showed preservation of the chondrocyte phenotype. In addition reduced proteoglycan synthesis and oversulfation of glycosaminoglycan chains were demonstrated, as already observed in primary chondrocytes from the Cant1 knock-out mouse. In conclusion, immortalized Cant1 knock-out chondrocytes maintained the disease phenotype observed in primary cells validating the in vitro model and providing an additional tool to further study the proteoglycan biosynthesis defect. The same approach might be extended to other cartilage disorders.


Asunto(s)
Ácido Anhídrido Hidrolasas/fisiología , Condrocitos/patología , Anomalías Craneofaciales/patología , Enanismo/patología , Glicosaminoglicanos/metabolismo , Inestabilidad de la Articulación/patología , Osificación Heterotópica/patología , Fenotipo , Polidactilia/patología , Animales , Línea Celular Transformada , Condrocitos/metabolismo , Anomalías Craneofaciales/etiología , Anomalías Craneofaciales/metabolismo , Enanismo/etiología , Enanismo/metabolismo , Inestabilidad de la Articulación/etiología , Inestabilidad de la Articulación/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Osificación Heterotópica/etiología , Osificación Heterotópica/metabolismo , Polidactilia/etiología , Polidactilia/metabolismo
12.
Genes (Basel) ; 12(7)2021 06 24.
Artículo en Inglés | MEDLINE | ID: mdl-34202629

RESUMEN

We report on two siblings suffering from different pathogenic conditions, born to consanguineous parents. A multigene panel for brain malformations and microcephaly identified the homozygous splicing variant NM_005886.3:c.1416+1del in the KATNB1 gene in the older sister. On the other hand, exome sequencing revealed the homozygous frameshift variant NM_005245.4:c.9729del in the FAT1 gene in the younger sister, who had a more complex phenotype: in addition to bilateral anophthalmia and heart defects, she showed a right split foot with 4 toes, 5 metacarpals, second toe duplication and preaxial polydactyly on the right hand. These features have been never reported before in patients with pathogenic FAT1 variants and support the role of this gene in the development of limb buds. Notably, each parent was heterozygous for both of these variants, which were ultra-rare and rare, respectively. This study raises awareness about the value of using whole exome/genome sequencing rather than targeted gene panels when testing affected offspring born to consanguineous couples. In this way, exomic data from the parents are also made available for carrier screening, to identify heterozygous pathogenetic and likely pathogenetic variants in genes responsible for other recessive conditions, which may pose a risk for subsequent pregnancies.


Asunto(s)
Adenosina Trifosfatasas/genética , Cadherinas/genética , Lisencefalia/genética , Microcefalia/genética , Polidactilia/genética , Pulgar/anomalías , Encéfalo/anomalías , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Preescolar , Consanguinidad , Exoma/genética , Femenino , Mutación del Sistema de Lectura/genética , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Lactante , Recién Nacido , Lisencefalia/diagnóstico por imagen , Lisencefalia/patología , Microcefalia/diagnóstico por imagen , Microcefalia/patología , Linaje , Fenotipo , Polidactilia/diagnóstico por imagen , Polidactilia/patología , Hermanos , Pulgar/diagnóstico por imagen , Pulgar/patología , Secuenciación del Exoma
13.
Am J Med Genet A ; 185(12): 3831-3837, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34296525

RESUMEN

Polydactyly is a hallmark of GLI3 pathogenic variants, with Greig cephalopolysyndactyly syndrome and Pallister-Hall syndrome being the two main associated clinical presentations. Homozygous GLI3 variants are rare instances in the literature, and mendelian dominance is the accepted framework for GLI3-related diseases. Herein, we report three unrelated probands, presenting with polydactyly, and homozygous variants in the GLI3 gene. First, a 10-year-old girl, whose parents were first-degree cousins, presented with bilateral postaxial polydactyly of the hands, developmental delay and multiple malformations. Second, a male newborn, whose parents were first-degree cousins, presented with isolated bilateral postaxial polysyndactyly of the hands and the feet. Third, an adult male, whose parents were first-degree cousins, had bilateral mesoaxial polydactyly of the hands, with severe intellectual disability and multiple malformations. All three probands carried homozygous GLI3 variants. Strikingly, the parents also carried the child's variant, in the heterozygous state, without any clinical sign of GLI3 disease. Given the clinical presentation of our patients, the rarity and predicted high pathogenicity of the variants observed, and the absence of other pathogenic variants, we suggest that these GLI3 homozygous variants are causal. Moreover, the parents were heterozygous for the observed variants, but were clinically unremarkable, suggesting that these variants are hypomorphic alleles.


Asunto(s)
Predisposición Genética a la Enfermedad , Proteínas del Tejido Nervioso/genética , Polidactilia/genética , Proteína Gli3 con Dedos de Zinc/genética , Adulto , Niño , Femenino , Heterocigoto , Homocigoto , Humanos , Recién Nacido , Masculino , Linaje , Polidactilia/patología
14.
Am J Med Genet A ; 185(9): 2719-2738, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34087052

RESUMEN

Cyclin D2 (CCND2) is a critical cell cycle regulator and key member of the cyclin D2-CDK4 (DC) complex. De novo variants of CCND2 clustering in the distal part of the protein have been identified as pathogenic causes of brain overgrowth (megalencephaly, MEG) and severe cortical malformations in children including the megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome. Megalencephaly-associated CCND2 variants are localized to the terminal exon and result in accumulation of degradation-resistant protein. We identified five individuals from three unrelated families with novel variants in the proximal region of CCND2 associated with microcephaly, mildly simplified cortical gyral pattern, symmetric short stature, and mild developmental delay. Identified variants include de novo frameshift variants and a dominantly inherited stop-gain variant segregating with the phenotype. This is the first reported association between proximal CCND2 variants and microcephaly, to our knowledge. This series expands the phenotypic spectrum of CCND2-related disorders and suggests that distinct classes of CCND2 variants are associated with reciprocal effects on human brain growth (microcephaly and megalencephaly due to possible loss or gain of protein function, respectively), adding to the growing paradigm of inverse phenotypes due to dysregulation of key brain growth genes.


Asunto(s)
Encéfalo/anomalías , Ciclina D2/genética , Hidrocefalia/patología , Megalencefalia/patología , Mutación , Polidactilia/patología , Polimicrogiria/patología , Adolescente , Adulto , Niño , Femenino , Humanos , Hidrocefalia/genética , Lactante , Masculino , Megalencefalia/genética , Polidactilia/genética , Polimicrogiria/genética
15.
Am J Med Genet A ; 185(10): 2888-2894, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34037314

RESUMEN

Ellis-van Creveld (EvC) syndrome is an autosomal recessive disease, characterized by ectodermal, skeletal, and cardiac anomalies. We report intrafamilial phenotypic variability in three new EvC syndrome cases. Affected males in this study showed only ectodermal abnormalities, whereas an affected female showed the classical presentation of EvC Syndrome, including bilateral postaxial polydactyly of hands and feet, and congenital heart defects. Whole exome sequencing was performed to identify the causative variant, followed by validation and segregation analysis using Sanger sequencing. A homozygous deletion variant (c.731_757del) was identified in exon 6 of the EVC gene (NM_153717.2). The identified variant is considered to be the most likely candidate variant for the EvC syndrome in the family based on previous reports validating the role of EVC variants in the EvC syndrome. The disease correctly segregated in the family members, as all affected members were homozygous, and obligate carriers were heterozygous. Our family is remarkable in highlighting the variable expressivity of the EvC phenotype within the same family, due to a homozygous deletion mutation in the EVC gene. The variable expressivity might be due to the hypomorphic nature of mutation, or the presence of additional variants in modifier genes or in the regulatory regions of the EVC/EVC2 genes.


Asunto(s)
Síndrome de Ellis-Van Creveld/genética , Cardiopatías Congénitas/genética , Proteínas de la Membrana/genética , Polidactilia/genética , Variación Biológica Poblacional/genética , Niño , Ectodermo/anomalías , Ectodermo/patología , Síndrome de Ellis-Van Creveld/diagnóstico , Síndrome de Ellis-Van Creveld/patología , Exones/genética , Femenino , Corazón/fisiopatología , Cardiopatías Congénitas/patología , Heterocigoto , Homocigoto , Humanos , Recién Nacido , Masculino , Linaje , Polidactilia/patología , Eliminación de Secuencia/genética , Esqueleto/anomalías , Esqueleto/patología , Secuenciación del Exoma
18.
J Plast Reconstr Aesthet Surg ; 74(9): 2156-2162, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-33558104

RESUMEN

PURPOSE: Central polydactyly of the foot is rare, with few reports on surgical methods and treatment indications. In this study, based on the experience of central polydactyly in our department, we will consider morphological classification and describe our treatment plan. METHOD: In this retrospective study, 11 patients (11 digits) with central polydactyly were identified among 136 patients of polydactyly of the foot (2009-2018). They were classified according to morphologic characteristics: type I, the duplicated digits are independent of each other; type II, digits of the same size are duplicated; and type III, digits of different sizes are duplicated. RESULTS: In morphologic classification, there were 4 cases of type II and 7 cases of type III, but there was no case of type I. For type II, surgery was performed using the Bilhaut-Cloquet (BC) procedure in 2 patients, bone-removing flap (flap) method in 1 patient, and simple ablation in 1 patient. For type III, surgery was performed using the BC procedure in 1 patient, flap method in 3 patients, simple ablation in 2 patients, and ligation in 1 patient with floating type. CONCLUSION: In order to obtain good cosmetic results in digits of morphologic classifications type II and III, it is necessary to select the surgical approach with careful consideration of every feature.


Asunto(s)
Procedimientos de Cirugía Plástica/métodos , Polidactilia/cirugía , Dedos del Pie/anomalías , Dedos del Pie/cirugía , Preescolar , Estética , Femenino , Humanos , Lactante , Masculino , Polidactilia/clasificación , Polidactilia/patología , Estudios Retrospectivos , Colgajos Quirúrgicos , Dedos del Pie/patología
19.
Eur J Med Genet ; 64(2): 104124, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33359164

RESUMEN

The combination of congenital heart defects and vertebral anomalies with or without additional abnormalities has been reported in many genetic disorders. We describe a family in which four consecutive pregnancies were characterized by the combination of fetal congenital heart malformations and vertebral anomalies. In addition, preaxial polydactyly was detected in one of the fetuses. Reanalysis of the non-diagnostic clinical exome data revealed compound heterozygous variants c.350del, p.(Gly117AlafsTer90) and c.757G > T, p.(Asp253Tyr) in ETV2 which have previously not been known to be associated with a phenotype in humans. In mice, Etv2 encodes an obligatory transcription factor involved in the generation of hematopoietic and endothelial cells. Its homozygous disruption results in embryonic lethality due to severe blood and vessel defects. The Etv2 promoter may be bound by Nkx2-5, a key transcription factor in heart development. Pathogenic variants in the NKx2-5 homolog in humans (NKX2-5) are related to congenital heart defects. The identification of additional fetuses or live-born individuals with biallelic pathogenic variants in ETV2 will shed further light on this presumably novel gene-phenotype association and on the full phenotypic spectrum.


Asunto(s)
Feto/anomalías , Cardiopatías Congénitas/genética , Polidactilia/genética , Columna Vertebral/anomalías , Factores de Transcripción/genética , Adulto , Alelos , Femenino , Eliminación de Gen , Pruebas Genéticas , Cardiopatías Congénitas/diagnóstico por imagen , Cardiopatías Congénitas/patología , Heterocigoto , Proteína Homeótica Nkx-2.5/genética , Proteína Homeótica Nkx-2.5/metabolismo , Humanos , Masculino , Mutación Missense , Linaje , Polidactilia/diagnóstico por imagen , Polidactilia/patología , Embarazo , Columna Vertebral/diagnóstico por imagen , Ultrasonografía Prenatal
20.
Am J Hum Genet ; 107(5): 977-988, 2020 11 05.
Artículo en Inglés | MEDLINE | ID: mdl-33058759

RESUMEN

PRKACA and PRKACB code for two catalytic subunits (Cα and Cß) of cAMP-dependent protein kinase (PKA), a pleiotropic holoenzyme that regulates numerous fundamental biological processes such as metabolism, development, memory, and immune response. We report seven unrelated individuals presenting with a multiple congenital malformation syndrome in whom we identified heterozygous germline or mosaic missense variants in PRKACA or PRKACB. Three affected individuals were found with the same PRKACA variant, and the other four had different PRKACB mutations. In most cases, the mutations arose de novo, and two individuals had offspring with the same condition. Nearly all affected individuals and their affected offspring shared an atrioventricular septal defect or a common atrium along with postaxial polydactyly. Additional features included skeletal abnormalities and ectodermal defects of variable severity in five individuals, cognitive deficit in two individuals, and various unusual tumors in one individual. We investigated the structural and functional consequences of the variants identified in PRKACA and PRKACB through the use of several computational and experimental approaches, and we found that they lead to PKA holoenzymes which are more sensitive to activation by cAMP than are the wild-type proteins. Furthermore, expression of PRKACA or PRKACB variants detected in the affected individuals inhibited hedgehog signaling in NIH 3T3 fibroblasts, thereby providing an underlying mechanism for the developmental defects observed in these cases. Our findings highlight the importance of both Cα and Cß subunits of PKA during human development.


Asunto(s)
Anomalías Múltiples/genética , Disfunción Cognitiva/genética , Subunidades Catalíticas de Proteína Quinasa Dependientes de AMP Cíclico/genética , Dedos/anomalías , Mutación de Línea Germinal , Defectos de los Tabiques Cardíacos/genética , Polidactilia/genética , Dedos del Pie/anomalías , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/patología , Adolescente , Adulto , Animales , Secuencia de Bases , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/patología , AMP Cíclico/metabolismo , Subunidades Catalíticas de Proteína Quinasa Dependientes de AMP Cíclico/química , Subunidades Catalíticas de Proteína Quinasa Dependientes de AMP Cíclico/deficiencia , Femenino , Dedos/patología , Regulación del Desarrollo de la Expresión Génica , Defectos de los Tabiques Cardíacos/diagnóstico , Defectos de los Tabiques Cardíacos/patología , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Holoenzimas/química , Holoenzimas/deficiencia , Holoenzimas/genética , Humanos , Recién Nacido , Masculino , Ratones , Modelos Moleculares , Mosaicismo , Células 3T3 NIH , Linaje , Polidactilia/diagnóstico , Polidactilia/patología , Estructura Secundaria de Proteína , Dedos del Pie/patología
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