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1.
Am J Med Genet A ; 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31654484

RESUMO

RATIONALE: Adams-Oliver syndrome (AOS) is a genetic disorder characterized by the association of aplasia cutis congenita (ACC), terminal transverse limb defect (TTLD), congenital cardiac malformation (CCM), and minor features, such as cutaneous, neurological, and hepatic abnormalities (HAs). The aim of the study is to emphasize phenotype-genotype correlations in AOS. METHODS: We studied 29 AOS patients. We recorded retrospectively detailed phenotype data, including clinical examination, biological analyses, and imaging. The molecular analysis was performed through whole exome sequencing (WES). RESULTS: Twenty-nine patients (100%) presented with ACC, the principal inclusion criteria in the study. Seventeen of twenty-one (81%) had cutis marmorata telangiectasia congenita, 16/26 (62%) had TTLD, 14/23 (61%) had CCM, 7/20 (35%) had HAs, and 9/27 (33%) had neurological findings. WES was performed in 25 patients. Fourteen of twenty-five (56%) had alterations in the genes already described in AOS. CCM and HAs are particularly associated with the NOTCH1 genotype. TTLD is present in patients with DOCK6 and EOGT alterations. Neurological findings of variable degree were associated sometimes with DOCK6 and NOTCH1 rarely with EOGT. CONCLUSION: AOS is characterized by a clinical and molecular variability. It appears that degrees of genotype-phenotype correlations exist for patients with identified pathogenic mutations, underlining the need to undertake a systematic but adjusted multidisciplinary assessment.

2.
Eur J Med Genet ; : 103729, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31319224

RESUMO

Non-ossifying fibromas are seen in different disorders recognizable by specific features. Indeed, osteoglophonic dysplasia (OD) is characterized by radiolucent bone lesions associated with severe short stature, dysmorphism and failure of dental eruption. This syndrome is caused by heterozygous activating mutations in the immunoglobulin-like D3 domain of the FGFR1 gene, encoding a tyrosine kinase. Here, we report three patients from the same family presenting with radiolucent bone lesions and teeth retentions. Exome sequencing allowed identification of a novel mutation c.917C > T, p. Pro306Leu in exon 7 of the FGFR1 gene. Our patients present with normal stature and no severe dysmorphism. This report describes a mild form of OD and expands the phenotype related to FGFR1 mutations. These findings emphasize the need to consider FGFR1 variants in the case of multiple non-ossifying bone lesions associated with dental eruption anomalies.

3.
Hum Mol Genet ; 28(16): 2720-2737, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31042281

RESUMO

Mutations in genes encoding components of the intraflagellar transport (IFT) complexes have previously been associated with a spectrum of diseases collectively termed ciliopathies. Ciliopathies relate to defects in the formation or function of the cilium, a sensory or motile organelle present on the surface of most cell types. IFT52 is a key component of the IFT-B complex and ensures the interaction of the two subcomplexes, IFT-B1 and IFT-B2. Here, we report novel IFT52 biallelic mutations in cases with a short-rib thoracic dysplasia (SRTD) or a congenital anomaly of kidney and urinary tract (CAKUT). Combining in vitro and in vivo studies in zebrafish, we showed that SRTD-associated missense mutation impairs IFT-B complex assembly and IFT-B2 ciliary localization, resulting in decreased cilia length. In comparison, CAKUT-associated missense mutation has a mild pathogenicity, thus explaining the lack of skeletal defects in CAKUT case. In parallel, we demonstrated that the previously reported homozygous nonsense IFT52 mutation associated with Sensenbrenner syndrome [Girisha et al. (2016) A homozygous nonsense variant in IFT52 is associated with a human skeletal ciliopathy. Clin. Genet., 90, 536-539] leads to exon skipping and results in a partially functional protein. Finally, our work uncovered a novel role for IFT52 in microtubule network regulation. We showed that IFT52 interacts and partially co-localized with centrin at the distal end of centrioles where it is involved in its recruitment and/or maintenance. Alteration of this function likely contributes to centriole splitting observed in Ift52-/- cells. Altogether, our findings allow a better comprehensive genotype-phenotype correlation among IFT52-related cases and revealed a novel, extra-ciliary role for IFT52, i.e. disruption may contribute to pathophysiological mechanisms.

4.
Am J Hum Genet ; 104(3): 422-438, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30773277

RESUMO

SPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessive inheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia. Here, we identified bi-allelic variants in TONSL, which encodes the Tonsoku-like DNA repair protein, in nine subjects (from eight families) with SPONASTRIME dysplasia, and four subjects (from three families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities, but no definitive metaphyseal striations at diagnosis. The finding of early embryonic lethality in a Tonsl-/- murine model and the discovery of reduced length, spinal abnormalities, reduced numbers of neutrophils, and early lethality in a tonsl-/- zebrafish model both support the hypomorphic nature of the identified TONSL variants. Moreover, functional studies revealed increased amounts of spontaneous replication fork stalling and chromosomal aberrations, as well as fewer camptothecin (CPT)-induced RAD51 foci in subject-derived cell lines. Importantly, these cellular defects were rescued upon re-expression of wild-type (WT) TONSL; this rescue is consistent with the hypothesis that hypomorphic TONSL variants are pathogenic. Overall, our studies in humans, mice, zebrafish, and subject-derived cell lines confirm that pathogenic variants in TONSL impair DNA replication and homologous recombination-dependent repair processes, and they lead to a spectrum of skeletal dysplasia phenotypes with numerous extra-skeletal manifestations.

5.
Am J Med Genet A ; 179(4): 639-644, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30767363

RESUMO

We report novel causative mutations in the IFT80 gene identified in four fetuses from two unrelated families with Beemer-Langer syndrome (BLS) or BLS-like phenotypes. We discuss the implication of the IFT80 gene in ciliopathies, and its diagnostic value for BLS among other SRPS.

6.
Matrix Biol ; 2018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30439444

RESUMO

Desbuquois dysplasia type 1 (DBQD1) is a chondrodysplasia caused by mutations in CANT1 gene encoding an ER/Golgi calcium activated nucleotidase 1 that hydrolyses UDP. Here, using Cant1 knock-in and knock-out mice recapitulating DBQD1 phenotype, we report that CANT1 plays a crucial role in cartilage proteoglycan synthesis and in endochondral ossification. Specifically, the glycosaminoglycan synthesis was decreased in chondrocytes from Cant1 knock-out mice and their hydrodynamic size was reduced, whilst the sulfation was increased and the overall proteoglycan secretion was delayed. Interestingly, knock-out chondrocytes had dilated ER cisternae suggesting delayed protein secretion and cellular stress; however, no canonical ER stress response was detected using microarray analysis, Xbp1 splicing and protein levels of BiP and ATF4. The observed proteoglycan defects caused deregulated chondrocyte proliferation and maturation in the growth plate resulting in the reduced skeletal growth. In conclusion, the pathogenic mechanism of DBQD1 comprises deregulated chondrocyte performance due to defective intracellular proteoglycan synthesis and altered proteoglycan properties in the extracellular matrix.

7.
Nat Commun ; 9(1): 3087, 2018 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-30082715

RESUMO

Skeletal dysplasia with multiple dislocations are severe disorders characterized by dislocations of large joints and short stature. The majority of them have been linked to pathogenic variants in genes encoding glycosyltransferases, sulfotransferases or epimerases required for glycosaminoglycan synthesis. Using exome sequencing, we identify homozygous mutations in SLC10A7 in six individuals with skeletal dysplasia with multiple dislocations and amelogenesis imperfecta. SLC10A7 encodes a 10-transmembrane-domain transporter located at the plasma membrane. Functional studies in vitro demonstrate that SLC10A7 mutations reduce SLC10A7 protein expression. We generate a Slc10a7-/- mouse model, which displays shortened long bones, growth plate disorganization and tooth enamel anomalies, recapitulating the human phenotype. Furthermore, we identify decreased heparan sulfate levels in Slc10a7-/- mouse cartilage and patient fibroblasts. Finally, we find an abnormal N-glycoprotein electrophoretic profile in patient blood samples. Together, our findings support the involvement of SLC10A7 in glycosaminoglycan synthesis and specifically in skeletal development.

9.
J Med Genet ; 55(4): 278-284, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29358272

RESUMO

BACKGROUND: Stüve-Wiedemann syndrome (SWS) is characterised by bowing of the lower limbs, respiratory distress and hyperthermia that are often responsible for early death. Survivors develop progressive scoliosis and spontaneous fractures. We previously identified LIFR mutations in most SWS cases, but absence of LIFR pathogenic changes in five patients led us to perform exome sequencing and to identify homozygosity for a FAM46A mutation in one case [p.Ser205Tyrfs*13]. The follow-up of this case supported a final diagnosis of osteogenesis imperfecta (OI), based on vertebral collapses and blue sclerae. METHODS AND RESULTS: This prompted us to screen FAM46A in 25 OI patients with no known mutations.We identified a homozygous deleterious variant in FAM46A in two affected sibs with typical OI [p.His127Arg]. Another homozygous variant, [p.Asp231Gly], also classed as deleterious, was detected in a patient with type III OI of consanguineous parents using homozygosity mapping and exome sequencing.FAM46A is a member of the superfamily of nucleotidyltransferase fold proteins but its exact function is presently unknown. Nevertheless, there are lines of evidence pointing to a relevant role of FAM46A in bone development. By RT-PCR analysis, we detected specific expression of FAM46A in human osteoblasts andinterestingly, a nonsense mutation in Fam46a has been recently identified in an ENU-derived (N-ethyl-N-nitrosourea) mouse model characterised by decreased body length, limb, rib, pelvis, and skull deformities and reduced cortical thickness in long bones. CONCLUSION: We conclude that FAM46A mutations are responsible for a severe form of OI with congenital bowing of the lower limbs and suggest screening this gene in unexplained OI forms.

10.
Sci Rep ; 7(1): 15995, 2017 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-29167536

RESUMO

The aim of this study was to develop and cross-validate two models to estimate total energy expenditure (TEE) based on respiration variables in healthy subjects during daily physical activities. Ninety-nine male and female subjects systematically varying in age (18-60 years) and body mass index (BMI; 17-36 kg*m-2) completed eleven aerobic activities with a portable spirometer as the criterion measure. Two models were developed using linear regression analyses with the data from 67 randomly selected subjects (50.0% female, 39.9 ± 11.8 years, 25.1 ± 5.2 kg*m-2). The models were cross-validated with the other 32 subjects (49% female, 40.4 ± 10.7 years, 24.7 ± 4.6 kg*m-2) by applying equivalence testing and Bland-and-Altman analyses. Model 1, estimating TEE based solely on respiratory volume, respiratory rate, and age, was significantly equivalent to the measured TEE with a systematic bias of 0.06 kJ*min-1 (0.22%) and limits of agreement of ±6.83 kJ*min-1. Model 1 was as accurate in estimating TEE as Model 2, which incorporated further information on activity categories, heart rate, sex, and BMI. The results demonstrated that respiration variables and age can be used to accurately determine daily TEE for different types of aerobic activities in healthy adults across a broad range of ages and body sizes.

11.
Hum Mutat ; 38(12): 1731-1739, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28869677

RESUMO

The SH2 domain containing inositol phosphatase 2 (SHIP2) dephosphorylates PI(3,4,5)P3 to generate PI(3,4)P2, a lipid involved in the control of cell migration and adhesion. The INPPL1 gene that encodes SHIP2 has been found to be mutated in several cases of opsismodysplasia (OPS), a rare autosomal recessive chondrodysplasia characterized by growth plate defects and delayed bone maturation. Reported mutations often result in premature stop codons or missense mutations in SHIP2 catalytic domain. SHIP2 biochemical properties are known from studies in cancer cells; its role in endochondral ossification is unknown. Here, we report two novel mutations in the INPPL1 gene and show that cell migration is very much decreased in fibroblasts derived from three OPS patients as compared with control individuals. In contrast, cell adhesion on fibronectin is increased in OPS fibroblasts. An inhibitory effect on migration was also observed when normal fibroblasts were incubated in the presence of a SHIP2 competitive inhibitor. We conclude that both migration and adhesion are very much disrupted in OPS-derived fibroblasts. It is suggested that signaling events linked to migration and particularly to adhesion, which are lost in OPS patients, would prevent normal endochondral ossification.


Assuntos
Adesão Celular/genética , Movimento Celular/genética , Osteocondrodisplasias/enzimologia , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/genética , Transdução de Sinais , Códon sem Sentido , Feminino , Fibroblastos/metabolismo , Genes Reporter , Homozigoto , Humanos , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/genética , Fenótipo , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/metabolismo , Gravidez
12.
J Hum Genet ; 62(2): 229-234, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27604558

RESUMO

Short stature homeobox gene (SHOX) is located in the pseudoautosomal region 1 of the sex chromosomes. It encodes a transcription factor implicated in the skeletal growth. Point mutations, deletions or duplications of SHOX or its transcriptional regulatory elements are associated with two skeletal dysplasias, Léri-Weill dyschondrosteosis (LWD) and Langer mesomelic dysplasia (LMD), as well as in a small proportion of idiopathic short stature (ISS) individuals. We have identified a total of 15 partial SHOX deletions and 13 partial SHOX duplications in LWD, LMD and ISS patients referred for routine SHOX diagnostics during a 10 year period (2004-2014). Subsequently, we characterized these alterations using MLPA (multiplex ligation-dependent probe amplification assay), fine-tiling array CGH (comparative genomic hybridation) and breakpoint PCR. Nearly half of the alterations have a distal or proximal breakpoint in intron 3. Evaluation of our data and that in the literature reveals that although partial deletions and duplications only account for a small fraction of SHOX alterations, intron 3 appears to be a breakpoint hotspot, with alterations arising by non-allelic homologous recombination, non-homologous end joining or other complex mechanisms.


Assuntos
Duplicação Gênica/genética , Transtornos do Crescimento/genética , Proteínas de Homeodomínio/genética , Osteocondrodisplasias/genética , Deleção de Sequência/genética , Sequência de Bases , Hibridização Genômica Comparativa , Humanos , Íntrons/genética , Reação em Cadeia da Polimerase Multiplex , Técnicas de Amplificação de Ácido Nucleico , Análise de Sequência de DNA , Proteína de Homoeobox de Baixa Estatura
14.
J Neuroeng Rehabil ; 12: 88, 2015 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-26410821

RESUMO

BACKGROUND: We evaluated the feasibility of an augmented robotics-assisted tilt table (RATT) for incremental cardiopulmonary exercise testing (CPET) and exercise training in dependent-ambulatory stroke patients. METHODS: Stroke patients (Functional Ambulation Category ≤ 3) underwent familiarization, an incremental exercise test (IET) and a constant load test (CLT) on separate days. A RATT equipped with force sensors in the thigh cuffs, a work rate estimation algorithm and real-time visual feedback to guide the exercise work rate was used. Feasibility assessment considered technical feasibility, patient tolerability, and cardiopulmonary responsiveness. RESULTS: Eight patients (4 female) aged 58.3 ± 9.2 years (mean ± SD) were recruited and all completed the study. For IETs, peak oxygen uptake (V'O2peak), peak heart rate (HRpeak) and peak work rate (WRpeak) were 11.9 ± 4.0 ml/kg/min (45 % of predicted V'O2max), 117 ± 32 beats/min (72 % of predicted HRmax) and 22.5 ± 13.0 W, respectively. Peak ratings of perceived exertion (RPE) were on the range "hard" to "very hard". All 8 patients reached their limit of functional capacity in terms of either their cardiopulmonary or neuromuscular performance. A ventilatory threshold (VT) was identified in 7 patients and a respiratory compensation point (RCP) in 6 patients: mean V'O2 at VT and RCP was 8.9 and 10.7 ml/kg/min, respectively, which represent 75 % (VT) and 85 % (RCP) of mean V'O2peak. Incremental CPET provided sufficient information to satisfy the responsiveness criteria and identification of key outcomes in all 8 patients. For CLTs, mean steady-state V'O2 was 6.9 ml/kg/min (49 % of V'O2 reserve), mean HR was 90 beats/min (56 % of HRmax), RPEs were > 2, and all patients maintained the active work rate for 10 min: these values meet recommended intensity levels for bouts of training. CONCLUSIONS: The augmented RATT is deemed feasible for incremental cardiopulmonary exercise testing and exercise training in dependent-ambulatory stroke patients: the approach was found to be technically implementable, acceptable to the patients, and it showed substantial cardiopulmonary responsiveness. This work has clinical implications for patients with severe disability who otherwise are not able to be tested.


Assuntos
Teste de Esforço/instrumentação , Testes de Função Respiratória/instrumentação , Robótica/instrumentação , Reabilitação do Acidente Vascular Cerebral , Exercício/fisiologia , Teste de Esforço/métodos , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória/métodos , Robótica/métodos
15.
Am J Hum Genet ; 97(2): 311-8, 2015 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-26166481

RESUMO

KIAA0586, the human ortholog of chicken TALPID3, is a centrosomal protein that is essential for primary ciliogenesis. Its disruption in animal models causes defects attributed to abnormal hedgehog signaling; these defects include polydactyly and abnormal dorsoventral patterning of the neural tube. Here, we report homozygous mutations of KIAA0586 in four families affected by lethal ciliopathies ranging from a hydrolethalus phenotype to short-rib polydactyly. We show defective ciliogenesis, as well as abnormal response to SHH-signaling activation in cells derived from affected individuals, consistent with a role of KIAA0586 in primary cilia biogenesis. Whereas centriolar maturation seemed unaffected in mutant cells, we observed an abnormal extended pattern of CEP290, a centriolar satellite protein previously associated with ciliopathies. Our data show the crucial role of KIAA0586 in human primary ciliogenesis and subsequent abnormal hedgehog signaling through abnormal GLI3 processing. Our results thus establish that KIAA0586 mutations cause lethal ciliopathies.


Assuntos
Proteínas de Ciclo Celular/genética , Transtornos da Motilidade Ciliar/genética , Códon sem Sentido/genética , Deformidades Congênitas da Mão/genética , Cardiopatias Congênitas/genética , Hidrocefalia/genética , Fenótipo , Síndrome de Costela Curta e Polidactilia/genética , Sequência de Bases , Transtornos da Motilidade Ciliar/patologia , Europa Oriental , Evolução Fatal , Efeito Fundador , Humanos , Funções Verossimilhança , Dados de Sequência Molecular , Linhagem , Análise de Sequência de DNA
16.
Nat Commun ; 6: 7074, 2015 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-26044572

RESUMO

The analysis of individuals with ciliary chondrodysplasias can shed light on sensitive mechanisms controlling ciliogenesis and cell signalling that are essential to embryonic development and survival. Here we identify TCTEX1D2 mutations causing Jeune asphyxiating thoracic dystrophy with partially penetrant inheritance. Loss of TCTEX1D2 impairs retrograde intraflagellar transport (IFT) in humans and the protist Chlamydomonas, accompanied by destabilization of the retrograde IFT dynein motor. We thus define TCTEX1D2 as an integral component of the evolutionarily conserved retrograde IFT machinery. In complex with several IFT dynein light chains, it is required for correct vertebrate skeletal formation but may be functionally redundant under certain conditions.


Assuntos
Dineínas/genética , Síndrome de Ellis-Van Creveld/genética , Flagelos/fisiologia , Animais , Chlamydomonas reinhardtii , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Camundongos , Mutação , Penetrância , Peixe-Zebra
17.
Hum Mutat ; 36(2): 187-90, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25504470

RESUMO

Cerebro-costo-mandibular syndrome (CCMS) is a developmental disorder characterized by the association of Pierre Robin sequence and posterior rib defects. Exome sequencing and Sanger sequencing in five unrelated CCMS patients revealed five heterozygous variants in the small nuclear ribonucleoprotein polypeptides B and B1 (SNRPB) gene. This gene includes three transcripts, namely transcripts 1 and 2, encoding components of the core spliceosomal machinery (SmB' and SmB) and transcript 3 undergoing nonsense-mediated mRNA decay. All variants were located in the premature termination codon (PTC)-introducing alternative exon of transcript 3. Quantitative RT-PCR analysis revealed a significant increase in transcript 3 levels in leukocytes of CCMS individuals compared to controls. We conclude that CCMS is due to heterozygous mutations in SNRPB, enhancing inclusion of a SNRPB PTC-introducing alternative exon, and show that this developmental disease is caused by defects in the splicing machinery. Our finding confirms the report of SNRPB mutations in CCMS patients by Lynch et al. (2014) and further extends the clinical and molecular observations.


Assuntos
Deficiência Intelectual/genética , Micrognatismo/genética , Costelas/anormalidades , Proteínas Centrais de snRNP/genética , Adolescente , Adulto , Sequência de Bases , Pré-Escolar , Estudos de Associação Genética , Heterozigoto , Humanos , Masculino , Mutação de Sentido Incorreto , Adulto Jovem
18.
Am J Hum Genet ; 95(6): 763-70, 2014 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-25480037

RESUMO

Catel-Manzke syndrome is characterized by Pierre Robin sequence and a unique form of bilateral hyperphalangy causing a clinodactyly of the index finger. We describe the identification of homozygous and compound heterozygous mutations in TGDS in seven unrelated individuals with typical Catel-Manzke syndrome by exome sequencing. Six different TGDS mutations were detected: c.892A>G (p.Asn298Asp), c.270_271del (p.Lys91Asnfs(∗)22), c.298G>T (p.Ala100Ser), c.294T>G (p.Phe98Leu), c.269A>G (p.Glu90Gly), and c.700T>C (p.Tyr234His), all predicted to be disease causing. By using haplotype reconstruction we showed that the mutation c.298G>T is probably a founder mutation. Due to the spectrum of the amino acid changes, we suggest that loss of function in TGDS is the underlying mechanism of Catel-Manzke syndrome. TGDS (dTDP-D-glucose 4,6-dehydrogenase) is a conserved protein belonging to the SDR family and probably plays a role in nucleotide sugar metabolism.


Assuntos
Deformidades Congênitas da Mão/genética , Oxirredutases/genética , Síndrome de Pierre Robin/genética , Adolescente , Adulto , Sequência de Aminoácidos , Pré-Escolar , Exoma/genética , Feminino , Deformidades Congênitas da Mão/enzimologia , Haplótipos , Heterozigoto , Homozigoto , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Oxirredutases/metabolismo , Linhagem , Síndrome de Pierre Robin/enzimologia , Alinhamento de Sequência , Análise de Sequência de DNA , Adulto Jovem
19.
Am J Hum Genet ; 94(3): 405-14, 2014 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-24581741

RESUMO

Desbuquois dysplasia (DBQD) is a severe condition characterized by short stature, joint laxity, and advanced carpal ossification. Based on the presence of additional hand anomalies, we have previously distinguished DBQD type 1 and identified CANT1 (calcium activated nucleotidase 1) mutations as responsible for DBQD type 1. We report here the identification of five distinct homozygous xylosyltransferase 1 (XYLT1) mutations in seven DBQD type 2 subjects from six consanguineous families. Among the five mutations, four were expected to result in loss of function and a drastic reduction of XYLT1 cDNA level was demonstrated in two cultured individual fibroblasts. Because xylosyltransferase 1 (XT-I) catalyzes the very first step in proteoglycan (PG) biosynthesis, we further demonstrated in the two individual fibroblasts a significant reduction of cellular PG content. Our findings of XYLT1 mutations in DBQD type 2 further support a common physiological basis involving PG synthesis in the multiple dislocation group of disorders. This observation sheds light on the key role of the XT-I during the ossification process.


Assuntos
Anormalidades Craniofaciais/genética , Nanismo/genética , Instabilidade Articular/genética , Mutação , Ossificação Heterotópica/genética , Pentosiltransferases/genética , Polidactilia/genética , Adolescente , Adulto , Osso e Ossos/metabolismo , Criança , Consanguinidade , DNA Complementar/metabolismo , Exoma , Feminino , Fibroblastos/metabolismo , Predisposição Genética para Doença , Homozigoto , Humanos , Masculino , Repetições de Microssatélites/genética , Pentosiltransferases/metabolismo , Proteoglicanas/metabolismo , Análise de Sequência de DNA
20.
Pediatr Blood Cancer ; 61(2): 302-5, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24106199

RESUMO

BACKGROUND: Microcephalic osteodysplastic primordial dwarfism type II (MOPD II) is a rare primordial dwarfism that is similar to Seckel syndrome. Seckel syndrome is known to be associated with various hematological abnormalities; however, hematological findings in MOPD II patients have not been previously reported. The present study aimed to describe the hematological findings in a series of eight patients with MOPD II from a single center. MATERIALS AND METHODS: The study included eight patients with MOPD II that were analyzed via molecular testing, and physical and laboratory examinations. RESULTS: Molecular testing showed that seven of the eight patients had pericentrin (PCNT) gene mutations. Hematological evaluation showed that 7 (87.5%) patients had thrombocytosis, 6 (75%) had leukocytosis, 5 (62.5%) had both leukocytosis and thrombocytosis, and 2 (25%) had anemia. CONCLUSIONS: We report leukocytosis and thrombocytosis as a common hematologic abnormality in patients with MOPD II. The present findings may improve our understanding of the potential function of the PCNT gene in hematopoietic cell proliferation and differentiation.


Assuntos
Anemia Ferropriva/etiologia , Antígenos/genética , Nanismo/complicações , Leucocitose/etiologia , Microcefalia/complicações , Mutação/genética , Osteocondrodisplasias/complicações , Trombocitose/etiologia , Anemia Ferropriva/diagnóstico , Criança , Pré-Escolar , Nanismo/genética , Feminino , Retardo do Crescimento Fetal/genética , Seguimentos , Humanos , Lactente , Leucocitose/diagnóstico , Masculino , Microcefalia/genética , Osteocondrodisplasias/genética , Prognóstico , Trombocitose/diagnóstico
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