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1.
PLoS One ; 15(3): e0230003, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32155193

RESUMO

Myotonic dystrophy type 1 (DM1) is an inherited neuromuscular disease which results from an expansion of repetitive DNA elements within the 3' untranslated region of the DMPK gene. Some patients develop multiple pilomatricomas as well as malignant tumors in other tissues. Mutations of the catenin-ß gene (CTNNB1) could be demonstrated in most non-syndromic pilomatricomas. In order to gain insight into the molecular mechanisms which might be responsible for the occurrence of multiple pilomatricomas and cancers in patients with DM1, we have sequenced the CTNNB1 gene of four pilomatricomas and of one pilomatrical carcinoma which developed in one patient with molecularly proven DM1 within 4 years. We further analyzed the pilomatrical tumors for microsatellite instability as well as by NGS for mutations in 161 cancer-associated genes. Somatic and independent point-mutations were detected at typical hotspot regions of CTNNB1 (S33C, S33F, G34V, T41I) while one mutation within CTNNB1 represented a duplication mutation (G34dup.). Pilomatricoma samples were analyzed for microsatellite instability and expression of mismatch repair proteins but no mutated microsatellites could be detected and expression of mismatch repair proteins MLH1, MSH2, MSH6, PMS2 was not perturbed. NGS analysis only revealed one heterozygous germline mutation c.8494C>T; p.(Arg2832Cys) within the ataxia telangiectasia mutated gene (ATM) which remained heterozygous in the pilomatrical tumors. The detection of different somatic mutations in different pilomatricomas and in the pilomatrical carcinoma as well as the observation that the patient developed multiple pilomatricomas and one pilomatrical carcinoma over a short time period strongly suggest that the patient displays a hypermutation phenotype. This hypermutability seems to be tissue and gene restricted. Simultaneous transcription of the mutated DMPK gene and the CTNNB1 gene in cycling hair follicles might constitute an explanation for the observed tissue and gene specificity of hypermutability observed in DM1 patients. Elucidation of putative mechanisms responsible for hypermutability in DM1 patients requires further research.


Assuntos
Análise Mutacional de DNA , Doenças do Cabelo/genética , Mutação , Distrofia Miotônica/complicações , Fenótipo , Pilomatrixoma/genética , Neoplasias Cutâneas/genética , Doenças do Cabelo/complicações , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Instabilidade de Microssatélites , Pilomatrixoma/complicações , Neoplasias Cutâneas/complicações , beta Catenina/genética
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(10): 993-995, 2019 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-31598943

RESUMO

OBJECTIVE: To explore the genetic etiology of a pedigree affected with tricho-rhino-phalangeal syndrome. METHODS: Next-generation sequencing (NGS) using a gene panel for hereditary osteopathies was carried out for the proband. Suspected mutation was validated in the proband and her parents by Sanger sequencing. RESULTS: A heterozygous frameshift variation c.1995dupA (p.Gly666Argfs*20) of the TRPS1 gene was detected in the proband but not in her parents. CONCLUSION: The novel c.1995dupA (p.Gly666Argfs*20) mutation of the TRPS1 gene probably underlies the disease in the proband.


Assuntos
Proteínas de Ligação a DNA/genética , Dedos/anormalidades , Mutação da Fase de Leitura , Doenças do Cabelo/genética , Síndrome de Langer-Giedion/genética , Nariz/anormalidades , Fatores de Transcrição/genética , Feminino , Humanos , Linhagem
3.
Am J Hum Genet ; 105(2): 434-440, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374204

RESUMO

Brittle and "tiger-tail" hair is the diagnostic hallmark of trichothiodystrophy (TTD), a rare recessive disease associated with a wide spectrum of clinical features including ichthyosis, intellectual disability, decreased fertility, and short stature. As a result of premature abrogation of terminal differentiation, the hair is brittle and fragile and contains reduced cysteine content. Hypersensitivity to UV light is found in about half of individuals with TTD; all of these individuals harbor bi-allelic mutations in components of the basal transcription factor TFIIH, and these mutations lead to impaired nucleotide excision repair and basal transcription. Different genes have been found to be associated with non-photosensitive TTD (NPS-TTD); these include MPLKIP (also called TTDN1), GTF2E2 (also called TFIIEß), and RNF113A. However, a relatively large group of these individuals with NPS-TTD have remained genetically uncharacterized. Here we present the identification of an NPS-TTD-associated gene, threonyl-tRNA synthetase (TARS), found by next-generation sequencing of a group of uncharacterized individuals with NPS-TTD. One individual has compound heterozygous TARS variants, c.826A>G (p.Lys276Glu) and c.1912C>T (p.Arg638∗), whereas a second individual is homozygous for the TARS variant: c.680T>C (p.Leu227Pro). We showed that these variants have a profound effect on TARS protein stability and enzymatic function. Our results expand the spectrum of genes involved in TTD to include genes implicated in amino acid charging of tRNA, which is required for the last step in gene expression, namely protein translation. We previously proposed that some of the TTD-specific features derive from subtle transcription defects as a consequence of unstable transcription factors. We now extend the definition of TTD from a transcription syndrome to a "gene-expression" syndrome.


Assuntos
Doenças do Cabelo/patologia , Mutação , Treonina-tRNA Ligase/genética , Síndromes de Tricotiodistrofia/patologia , Alelos , Sequência de Aminoácidos , Estudos de Casos e Controles , Doenças do Cabelo/genética , Humanos , Fenótipo , Homologia de Sequência , Fator de Transcrição TFIIH/genética , Síndromes de Tricotiodistrofia/genética
4.
Artigo em Inglês | MEDLINE | ID: mdl-31343132

RESUMO

Trichorhinophalangeal syndrome (TRPS) is rare genetic disorder with autosomal dominant inheritance. The TRPS1 gene is located on the long arm of the eighth chromosome (8q24.12). The phenotype is variable and presents a wide clinical spectrum. Most cases are characterised by thin, sparse scalp hair, distinctive facial dysmorphism, and various skeletal abnormalities, especially of the hands and feet. Characteristic facial features may include a "pear-shaped" nose, micrognathia, dental anomalies, prominent ears, elongated philtrum, and thin upper vermillion border. In most cases, affected individuals exhibit skeletal abnormalities including brachydactyly and clinodac-tyly, short metacarpals phalanges, short feet and metatarsals, and pectus carinatum and hip joint malformations. Additionally, patients may exhibit short stature. This report presents four cases of TRPS (three sporadic and one familial). Clinical presentation included typical facial features and vari-ous skeletal abnormalities. Some TRPS symptoms may mimic growth hormone deficiency and other endocrine disturbances. The aim of this article is to deliver TRPS symptomatology. The treatment of TRPS is symptomatic and supportive and requires the coordination of several specialists, including paediatricians, endocrinologists, orthopaedic surgeons, dermatologists, and medical rehabilitation and den-tal specialists. In some cases, recombinant growth hormone therapy may be necessary. Genetic counselling may be of benefit for affect-ed individuals and their families.


Assuntos
Dedos/anormalidades , Doenças do Cabelo/diagnóstico , Síndrome de Langer-Giedion/diagnóstico , Nariz/anormalidades , Adolescente , Criança , Pré-Escolar , Feminino , Dedos/patologia , Doenças do Cabelo/genética , Doenças do Cabelo/patologia , Doenças do Cabelo/terapia , Humanos , Síndrome de Langer-Giedion/genética , Síndrome de Langer-Giedion/patologia , Síndrome de Langer-Giedion/terapia , Masculino , Mutação , Nariz/patologia , Fenótipo , Polônia , Proteínas Repressoras/genética
5.
Hautarzt ; 70(7): 514-519, 2019 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-31197391

RESUMO

Genetic diseases with hyper- and hypotrichosis are very heterogeneous, both clinically and genetically. This is especially true for ectodermal dysplasias but also for hereditary syndromes in which, beyond abnormal hair growth, other structures and organs are affected. In this review, we discuss distinct diseases with excessive and reduced hair growth, focusing on the clinical hallmarks and underlying genetic defects.


Assuntos
Doenças do Cabelo/genética , Displasia Ectodérmica/genética , Cabelo , Humanos , Hipotricose/genética , Síndrome
8.
Int J Dermatol ; 58(8): 946-952, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31077348

RESUMO

BACKGROUND: Autosomal recessive wooly hair/hypotrichosis is an inherited disorder of hair characterized by less dense, short, and tightly curled hair on the scalp and sometimes less dense to complete absence of eyebrows and eyelashes. Autosomal recessive wooly hair/hypotrichosis phenotypes are mostly associated with pathogenic sequence variants in LIPH and LPAR6 genes. METHODS: To find out the molecular basis of the disease, five families with autosomal recessive wooly hair/hypotrichosis were recruited for genetic analysis. Direct Sanger sequencing of LIPH and LPAR6 genes was carried out using BigDye chain termination chemistry. P2RY5 protein homology models were developed to study the effect of mutation on protein structure in a family having novel mutation. RESULTS: Sanger sequencing revealed a novel homozygous missense mutation (c.47A>T) in the LPAR6 gene in family A, while recurrent mutation (c.436G>A) was detected in the rest of the four families (B-E). Protein homology models for both native and mutant P2RY5 protein were developed to study the difference in subtle structural features because of Lys16Met (K16M) mutation. We observed that P2RY5K16M mutation results decrease in the number of ionic interactions detrimental to the protein stability. Protein modeling studies revealed that the novel mutation identified here decreased the number of ionic interactions by affecting physicochemical parameters of the protein, leading to an overall decrease in protein stability with no major secondary structural changes. CONCLUSION: The molecular analysis further confirms the frequent involvement of LPAR6 in autosomal recessive wooly hair/hypotrichosis, while the bioinformatic study revealed that the missense mutation destabilizes the overall structure of P2RY5 protein.


Assuntos
Genes Recessivos/genética , Doenças do Cabelo/genética , Cabelo/anormalidades , Hipotricose/genética , Receptores de Ácidos Lisofosfatídicos/genética , Biologia Computacional , Consanguinidade , Feminino , Humanos , Masculino , Mutação de Sentido Incorreto , Paquistão , Linhagem , Fenótipo , Estrutura Secundária de Proteína/genética , Receptores de Ácidos Lisofosfatídicos/química , Receptores Purinérgicos P2/química , Receptores Purinérgicos P2/genética , Homologia de Sequência de Aminoácidos
9.
Gene ; 699: 110-114, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30844479

RESUMO

Tricho-hepatic-enteric syndrome (THES) is a genetically heterogeneous rare syndrome (OMIM: 222470 (THES1) and 614602 (THES2)) that typically presents in the neonatal period with intractable diarrhoea, intra-uterine growth retardation (IUGR), facial dysmorphism, and hair and skin changes. THES is associated with pathogenic variants in either TTC37 or SKIV2L; both are components of the human SKI complex, an RNA exosome cofactor. We report an 8 year old girl who was diagnosed with THES by the Undiagnosed Disease Program-WA with compound heterozygous pathogenic variants in SKIV2L. While THES was considered in the differential diagnosis, the absence of protracted diarrhoea delayed definitive diagnosis. We therefore suggest that SKIV2L testing should be considered in cases otherwise suggestive of THES, but without the characteristic diarrhoea. We expand the phenotypic spectrum while reviewing the current knowledge on SKIV2L.


Assuntos
Diarreia Infantil/diagnóstico , Diarreia Infantil/genética , Diarreia/diagnóstico , Diarreia/genética , Retardo do Crescimento Fetal/diagnóstico , Retardo do Crescimento Fetal/genética , Doenças do Cabelo/diagnóstico , Doenças do Cabelo/genética , DNA Helicases/genética , Facies , Heterozigoto , Humanos
10.
Mol Genet Metab ; 126(4): 504-512, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30691926

RESUMO

Mutations of the TRPS1 gene cause trichorhinophalangeal syndrome (TRPS), a skeletal dysplasia with dental abnormalities. TRPS dental phenotypes suggest that TRPS1 regulates multiple aspects of odontogenesis, including the tooth number and size. Previous studies delineating Trps1 expression throughout embryonic tooth development in mice detected strong Trps1 expression in dental mesenchyme, preodontoblasts, and dental follicles, suggesting that TRPS dental phenotypes result from abnormalities in early developmental processes. In this study, Trps1+/- and Trps1-/- mice were analyzed to determine consequences of Trps1 deficiency on odontogenesis. We focused on the aspects of tooth formation that are disturbed in TRPS and on potential molecular abnormalities underlying TRPS dental phenotypes. Microcomputed tomography analyses of molars were used to determine tooth size, crown shape, and mineralization of dental tissues. These analyses uncovered that disruption of one Trps1 allele is sufficient to impair mineralization of dentin in both male and female mice. Enamel mineral density was decreased only in males, while mineralization of the root dental tissues was decreased only in females. In addition, significantly smaller teeth were detected in Trps1+/- females. Histomorphometric analyses of tooth organs showed reduced anterior-posterior diameter in Trps1-/- mice. BrdU-incorporation assay detected reduced proliferation of mesenchymal and epithelial cells in Trps1-/- tooth organs. Immunohistochemistry for Runx2 and Osx osteogenic transcription factors revealed changes in their spatial distribution in Trps1-/- tooth organs and uncovered cell-type specific requirements of Trps1 for Osx expression. In conclusion, this study has demonstrated that Trps1 is a positive regulator of cell proliferation in both dental mesenchyme and epithelium, suggesting that the microdontia in TRPS is likely due to decreased cell proliferation in developing tooth organs. Furthermore, the reduced mineralization observed in Trps1+/- mice may provide some explanation for the extensive dental caries reported in TRPS patients.


Assuntos
Proliferação de Células , Fatores de Transcrição GATA/genética , Regulação da Expressão Gênica , Odontogênese , Calcificação de Dente , Alelos , Animais , Diferenciação Celular , Cárie Dentária/etiologia , Células Epiteliais , Feminino , Dedos/anormalidades , Doenças do Cabelo/complicações , Doenças do Cabelo/genética , Síndrome de Langer-Giedion/complicações , Síndrome de Langer-Giedion/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dente Molar/patologia , Nariz/anormalidades , Microtomografia por Raio-X
15.
Oral Dis ; 25(1): 182-191, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30095208

RESUMO

OBJECTIVES: Variants in DLX3 cause tricho-dento-osseous syndrome (TDO, MIM #190320), a systemic condition with hair, nail and bony changes, taurodontism and amelogenesis imperfecta (AI), inherited in an autosomal dominant fashion. Different variants found within this gene are associated with different phenotypic presentations. To date, six different DLX3 variants have been reported in TDO. The aim of this paper was to explore and discuss three recently uncovered new variants in DLX3. SUBJECTS AND METHODS: Whole-exome sequencing identified a new DLX3 variant in one family, recruited as part of an ongoing study of genetic variants associated with AI. Targeted clinical exome sequencing of two further families revealed another new variant of DLX3 and complete heterozygous deletion of DLX3. For all three families, the phenotypes were shown to consist of AI and taurodontism, together with other attenuated features of TDO. RESULTS: c.574delG p.(E192Rfs*66), c.476G>T (p.R159L) and a heterozygous deletion of the entire DLX3 coding region were identified in our families. CONCLUSION: These previously unreported variants add to the growing literature surrounding AI, allowing for more accurate genetic testing and better understanding of the associated clinical consequences.


Assuntos
Amelogênese Imperfeita/genética , Anormalidades Craniofaciais/genética , Hipoplasia do Esmalte Dentário/genética , Doenças do Cabelo/genética , Proteínas de Homeodomínio/genética , Fatores de Transcrição/genética , Feminino , Humanos , Masculino , Linhagem
18.
BMC Med Genet ; 19(1): 211, 2018 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-30541476

RESUMO

BACKGROUND: Tricho-rhino-phalangeal syndrome (TRPS) is a rare autosomal dominant genetic disorder characterized by distinctive craniofacial and skeletal abnormalities, while non-ossifying fibroma (NOF) is a common benign bone tumour in children and adolescents. To date, no case of TRPS coexisting with NOF has been reported. This report presents a 12-year-old girl who had the characteristic features of tricho-rhino-phalangeal syndrome and non-ossifying fibroma with a fibula fracture. CASE PRESENTATION: A 12-year-old girl was admitted to the Department of Endocrinology and Diabetes for evaluation of brachydactyly and a right fibula fracture. Clinical examination revealed sparse scalp hair, a characteristic bulbous pear-shaped nose, and brachydactyly with significant shortening of the fourth metatarsal. Neither intellectual disability nor multiple exostoses were observed. Radiography of both hands showed brachydactyly and cone-shaped epiphyses of the middle phalanges of the digits of both hands with deviation of the phalangeal axis. Genetic analysis of TRPS1 identified a heterozygous germline sequence variant (p.Ala932Thr) in exon 6 in the girl and her father. Approximately 1 month before being admitted to our department, the girl experienced a minor fall and suffered a fracture of the proximal fibula in the right lower limb. The pathological cytological diagnosis of the osteolytic lesion was NOF. Ten months following the surgery, the lesion on the proximal fibula of the girl disappeared. CONCLUSIONS: In conclusion, the present study is the first to report a rare case of NOF with a pathologic fracture in the fibula of a girl with TRPS. The identification of a missense mutation, (p.Ala932Thr), in exon 6 of TRPS1 in this kindred further suggested that the patient had type I TRPS and indicated that mutations in this exon may be correlated with more pronounced features of the syndrome. Radiological techniques and genetic analysis played key roles in the definitive diagnosis.


Assuntos
Neoplasias Ósseas/genética , Braquidactilia/genética , Proteínas de Ligação a DNA/genética , Fibroma/genética , Dedos/anormalidades , Fraturas Espontâneas/genética , Doenças do Cabelo/genética , Síndrome de Langer-Giedion/genética , Neoplasias/genética , Nariz/anormalidades , Fatores de Transcrição/genética , Adulto , Sequência de Bases , Neoplasias Ósseas/complicações , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/patologia , Braquidactilia/complicações , Braquidactilia/diagnóstico por imagem , Braquidactilia/patologia , Criança , Éxons , Feminino , Fibroma/complicações , Fibroma/diagnóstico por imagem , Fibroma/patologia , Fíbula/lesões , Dedos/diagnóstico por imagem , Dedos/patologia , Fraturas Espontâneas/complicações , Fraturas Espontâneas/diagnóstico por imagem , Fraturas Espontâneas/patologia , Expressão Gênica , Doenças do Cabelo/complicações , Doenças do Cabelo/diagnóstico por imagem , Doenças do Cabelo/patologia , Humanos , Síndrome de Langer-Giedion/complicações , Síndrome de Langer-Giedion/diagnóstico por imagem , Síndrome de Langer-Giedion/patologia , Masculino , Mutação , Neoplasias/complicações , Neoplasias/diagnóstico por imagem , Neoplasias/patologia , Nariz/diagnóstico por imagem , Nariz/patologia , Herança Paterna , Radiografia
19.
Am J Hum Genet ; 103(5): 777-785, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30401459

RESUMO

Hypotrichosis simplex (HS) is a rare form of hereditary alopecia characterized by childhood onset of diffuse and progressive scalp and body hair loss. Although research has identified a number of causal genes, genetic etiology in about 50% of HS cases remains unknown. The present report describes the identification via whole-exome sequencing of five different mutations in the gene LSS in three unrelated families with unexplained, potentially autosomal-recessive HS. Affected individuals showed sparse to absent lanugo-like scalp hair, sparse and brittle eyebrows, and sparse eyelashes and body hair. LSS encodes lanosterol synthase (LSS), which is a key enzyme in the cholesterol biosynthetic pathway. This pathway plays an important role in hair follicle biology. After localizing LSS protein expression in the hair shaft and bulb of the hair follicle, the impact of the mutations on keratinocytes was analyzed using immunoblotting and immunofluorescence. Interestingly, wild-type LSS was localized in the endoplasmic reticulum (ER), whereas mutant LSS proteins were localized in part outside of the ER. A plausible hypothesis is that this mislocalization has potential deleterious implications for hair follicle cells. Immunoblotting revealed no differences in the overall level of wild-type and mutant protein. Analyses of blood cholesterol levels revealed no decrease in cholesterol or cholesterol intermediates, thus supporting the previously proposed hypothesis of an alternative cholesterol pathway. The identification of LSS as causal gene for autosomal-recessive HS highlights the importance of the cholesterol pathway in hair follicle biology and may facilitate novel therapeutic approaches for hair loss disorders in general.


Assuntos
Genes Recessivos/genética , Transferases Intramoleculares/genética , Mutação/genética , Adolescente , Adulto , Alelos , Alopecia/genética , Colesterol/genética , Retículo Endoplasmático/genética , Feminino , Cabelo/anormalidades , Doenças do Cabelo/genética , Humanos , Hipotricose/genética , Queratinócitos/patologia , Masculino , Linhagem , Adulto Jovem
20.
Ital J Pediatr ; 44(1): 138, 2018 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-30458885

RESUMO

BACKGROUND: Trichorhinophalangeal syndrome (TRPS) is a rare autosomal dominant disorder caused by defects involving the TRPS1 gene. It exhibits distinctive craniofacial, ectodermal and skeletal abnormalities, such as sparse hair, bulbous nasal tip and short deformed fingers, with extremely variable expressivity. CASE PRESENTATION: We report the case of a 17 months old girl, who presented growth retardation and dysmorphic features. Postnatal growth was always below - 2 Standard Deviation for both weight and length and physical examination revealed relative macrocephaly, sparse hair, bulbous nasal tip, thin upper lip, protruding ears, prominent forehead, small jaw, and short hands and feet. Patient's mother shared the same facial features, and presented sparse hair and small hands. The maternal grandfather and two uncles presented short stature, bulbous nasal tip, thin hair, and premature alopecia. Molecular analysis of TRPS1 gene showed a heterozygous c.2086C > T;(p.Arg696Ter) mutation both in the patient and her mother, confirming the diagnosis of TRPS, type I. CONCLUSIONS: Clinical phenotype of TRPS can be subtle and the syndrome often remains undiagnosed. A comprehensive clinical examination and an exhaustive family history are crucial to reach the correct diagnosis, which is essential to perform adequate follow-up and timely therapeutic procedures.


Assuntos
Dedos/anormalidades , Doenças do Cabelo/diagnóstico , Síndrome de Langer-Giedion/diagnóstico , Nariz/anormalidades , Proteínas de Ligação a DNA/genética , Diagnóstico Precoce , Feminino , Doenças do Cabelo/genética , Heterozigoto , Humanos , Lactente , Síndrome de Langer-Giedion/genética , Mutação , Fatores de Transcrição/genética
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