RESUMEN
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.
Asunto(s)
Genes Recesivos/genética , Transferasas Intramoleculares/genética , Mutación/genética , Adolescente , Adulto , Alelos , Alopecia/genética , Colesterol/genética , Retículo Endoplásmico/genética , Femenino , Cabello/anomalías , Enfermedades del Cabello/genética , Humanos , Hipotricosis/genética , Queratinocitos/patología , Masculino , Linaje , Adulto JovenRESUMEN
TP63-related disorders comprise a group of six overlapping autosomal dominant (AD) syndromes caused by heterozygous pathogenic variants in the tumor protein p63 gene (TP63). The present report describes the identification of heterozygous de novo pathogenic variants in the DNA binding domain (DBD) of the TP63 gene in two patients diagnosed with Ectodermal dysplasia-Ectrodactyly-Cleft lip/palate syndrome three (EEC3) and Ankyloblepharon-Ectodermal defects-Cleft lip/palate syndrome (AEC), respectively. The report discusses the phenotypic and genotypic characteristics of these patients and provides a brief review of the TP63-related disorder literature.
Asunto(s)
Labio Leporino/genética , Fisura del Paladar/genética , Displasia Ectodérmica/genética , Anomalías del Ojo/genética , Párpados/anomalías , Discapacidad Intelectual/genética , Sindactilia/genética , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Niño , Femenino , Genotipo , Heterocigoto , Humanos , Recién Nacido , Fenotipo , Fotograbar , SíndromeRESUMEN
Dystrophic epidermolysis bullosa is an inherited skin disorder characterized by fragile skin that is prone to blistering. We report here a consanguineous Pakistani family with two siblings, in whom a severe recessive dystrophic epidermolysis bullosa was suspected. Using whole-exome sequencing for one sibling, the homozygous base substitution c.7249C>G in COL7A1 was identified, and could be confirmed in the other sibling by Sanger sequencing. In our exome data, this mutation was annotated as a missense substitution (p.Gln2417Glu), but in silico tools indicated a possible effect on splicing. Using the ExonTrap vector it was verified that the mutation leads to activation of a cryptic donor splice site, which leads to loss of 26 nucleotides, and a frame-shift event predicted to result in a truncated protein (p.Q2417Sfs*57). The present report de-scribes an apparent COL7A1 missense substitution with an unexpected consequence on splicing that leads to a severe recessive dystrophic epidermolysis bullosa phenotype.
Asunto(s)
Epidermólisis Ampollosa Distrófica , Colágeno/genética , Colágeno Tipo VII/genética , Epidermólisis Ampollosa Distrófica/diagnóstico , Epidermólisis Ampollosa Distrófica/genética , Genes Recesivos , Humanos , Mutación , Mutación Missense , Empalme del ARNRESUMEN
Uncombable hair syndrome (UHS), also known as "spun glass hair syndrome," "pili trianguli et canaliculi," or "cheveux incoiffables" is a rare anomaly of the hair shaft that occurs in children and improves with age. UHS is characterized by dry, frizzy, spangly, and often fair hair that is resistant to being combed flat. Until now, both simplex and familial UHS-affected case subjects with autosomal-dominant as well as -recessive inheritance have been reported. However, none of these case subjects were linked to a molecular genetic cause. Here, we report the identification of UHS-causative mutations located in the three genes PADI3 (peptidylarginine deiminase 3), TGM3 (transglutaminase 3), and TCHH (trichohyalin) in a total of 11 children. All of these individuals carry homozygous or compound heterozygous mutations in one of these three genes, indicating an autosomal-recessive inheritance pattern in the majority of UHS case subjects. The two enzymes PADI3 and TGM3, responsible for posttranslational protein modifications, and their target structural protein TCHH are all involved in hair shaft formation. Elucidation of the molecular outcomes of the disease-causing mutations by cell culture experiments and tridimensional protein models demonstrated clear differences in the structural organization and activity of mutant and wild-type proteins. Scanning electron microscopy observations revealed morphological alterations in hair coat of Padi3 knockout mice. All together, these findings elucidate the molecular genetic causes of UHS and shed light on its pathophysiology and hair physiology in general.
Asunto(s)
Antígenos/genética , Enfermedades del Cabello/genética , Cabello/crecimiento & desarrollo , Hidrolasas/genética , Proteínas de Filamentos Intermediarios/genética , Mutación , Transglutaminasas/genética , Adolescente , Animales , Secuencia de Bases , Línea Celular , Codón sin Sentido , Femenino , Cabello/anomalías , Cabello/anatomía & histología , Cabello/metabolismo , Humanos , Hidrolasas/deficiencia , Hidrolasas/metabolismo , Masculino , Ratones , Ratones Noqueados , Modelos Moleculares , Mutación Missense/genética , Conformación Proteica , Arginina Deiminasa Proteína-Tipo 3 , Desiminasas de la Arginina Proteica , Transglutaminasas/deficiencia , Transglutaminasas/metabolismo , Vibrisas/anomalíasRESUMEN
Dowling-Degos disease (DDD) is an autosomal-dominant genodermatosis characterized by progressive and disfiguring reticulate hyperpigmentation. We previously identified loss-of-function mutations in KRT5 but were only able to detect pathogenic mutations in fewer than half of our subjects. To identify additional causes of DDD, we performed exome sequencing in five unrelated affected individuals without mutations in KRT5. Data analysis identified three heterozygous mutations from these individuals, all within the same gene. These mutations, namely c.11G>A (p.Trp4*), c.652C>T (p.Arg218*), and c.798-2A>C, are within POGLUT1, which encodes protein O-glucosyltransferase 1. Further screening of unexplained cases for POGLUT1 identified six additional mutations, as well as two of the above described mutations. Immunohistochemistry of skin biopsies of affected individuals with POGLUT1 mutations showed significantly weaker POGLUT1 staining in comparison to healthy controls with strong localization of POGLUT1 in the upper parts of the epidermis. Immunoblot analysis revealed that translation of either wild-type (WT) POGLUT1 or of the protein carrying the p.Arg279Trp substitution led to the expected size of about 50 kDa, whereas the c.652C>T (p.Arg218*) mutation led to translation of a truncated protein of about 30 kDa. Immunofluorescence analysis identified a colocalization of the WT protein with the endoplasmic reticulum and a notable aggregating pattern for the truncated protein. Recently, mutations in POFUT1, which encodes protein O-fucosyltransferase 1, were also reported to be responsible for DDD. Interestingly, both POGLUT1 and POFUT1 are essential regulators of Notch activity. Our results furthermore emphasize the important role of the Notch pathway in pigmentation and keratinocyte morphology.
Asunto(s)
Glucosiltransferasas/genética , Hiperpigmentación/genética , Mutación , Enfermedades Cutáneas Genéticas/genética , Enfermedades Cutáneas Papuloescamosas/genética , Adolescente , Adulto , Exoma , Femenino , Estudio de Asociación del Genoma Completo , Heterocigoto , Humanos , Queratinocitos/citología , Queratinocitos/metabolismo , Masculino , Persona de Mediana Edad , Linaje , Conformación Proteica , Análisis de Secuencia de ADN , Piel/patología , Adulto JovenRESUMEN
Richner-Hanhart syndrome (RHS, tyrosinemia type II) is a rare, autosomal recessive inborn error of tyrosine metabolism caused by tyrosine aminotransferase deficiency. It is characterized by photophobia due to keratitis, painful palmoplantar hyperkeratosis, variable mental retardation, and elevated serum tyrosine levels. Patients are often misdiagnosed with herpes simplex keratitis. We report on a a boy from Brazil who presented with bilateral keratitis secondary to RHS, which had earlier been misdiagnosed as herpes simplex keratitis.
Asunto(s)
Queratitis/diagnóstico , Queratodermia Palmoplantar/diagnóstico , Tirosinemias/diagnóstico , Brasil , Preescolar , Humanos , MasculinoAsunto(s)
Hiperpigmentación , Anomalías Cutáneas , Femenino , Humanos , Hiperpigmentación/diagnósticoRESUMEN
Three children from an expanded consanguineous Kuwaiti kindred presented with ankyloblepharon, sparse and curly hair, and hypoplastic nails, suggestive of CHAND syndrome (OMIM 214350) that belongs to the heterogeneous spectrum of ectodermal dysplasias. After exclusion of pathogenic mutations in TP63 we performed homozygosity mapping, followed by exome sequencing of one affected individual. We initially identified three homozygous mutations in the linked region, located in PWP2, MX2 and RIPK4. Recently, mutations in RIPK4 have been reported in Bartsocas-Papas syndrome (OMIM 263650) that shows overlapping clinical symptoms with the phenotype observed in the affected individuals studied here. Subsequent analysis of affected and non-affected family members showed that mutation c.850G>A (p.Glu284Lys) in RIPK4 was in complete segregation with the disease phenotype, in accordance with an autosomal recessive inheritance pattern, thus supporting pathogenicity of this variant. Interestingly, however, our patients did not have cleft lip/palate, a common feature encountered in Bartsocas-Papas syndrome. Whereas in Bartsocas-Papas syndromes missense mutations are usually located within the serin/threonin kinase of RIPK4, the mutation detected in our family resides just outside of the kinase domain, which could explain the milder phenotype. Our data raise the question if CHAND syndrome indeed is a distinct entity. Alternatively, CHAND and Bartsocas-Papas syndrome might be allelic disorders or RIPK4 mutations could confer varying degrees of phenotypic severity, depending on their localization within or outside functionally important domains. Our findings indicate that making an accurate diagnosis based only on the prevailing clinical symptoms is challenging.
Asunto(s)
Labio Leporino/complicaciones , Labio Leporino/genética , Fisura del Paladar/complicaciones , Fisura del Paladar/genética , Anomalías del Ojo/complicaciones , Anomalías del Ojo/genética , Enfermedades de los Párpados/complicaciones , Enfermedades de los Párpados/genética , Enfermedades del Cabello/complicaciones , Enfermedades del Cabello/genética , Rodilla/anomalías , Mutación/genética , Uñas Malformadas/complicaciones , Uñas Malformadas/genética , Proteínas Serina-Treonina Quinasas/genética , Sindactilia/complicaciones , Sindactilia/genética , Secuencia de Aminoácidos , Secuencia de Bases , Secuencia Conservada , Análisis Mutacional de ADN , Evolución Molecular , Exoma/genética , Femenino , Humanos , Masculino , Modelos Moleculares , Datos de Secuencia Molecular , Linaje , Fenotipo , Proteínas Serina-Treonina Quinasas/química , Homología Estructural de Proteína , Síndrome , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
The soil microbe Corynebacterium glutamicum is a leading workhorse in industrial biotechnology and has become famous for its power to synthetise amino acids and a range of bulk chemicals at high titre and yield. The product portfolio of the microbe is continuously expanding. Moreover, metabolically engineered strains of C. glutamicum produce more than 30 high value active ingredients, including signature molecules of raspberry, savoury, and orange flavours, sun blockers, anti-ageing sugars, and polymers for regenerative medicine. Herein, we highlight recent advances in engineering of the microbe into novel cell factories that overproduce these precious molecules from pioneering proofs-of-concept up to industrial productivity.
Asunto(s)
Corynebacterium glutamicum , Aminoácidos/metabolismo , Biotecnología , Corynebacterium glutamicum/genética , Corynebacterium glutamicum/metabolismo , Humanos , Ingeniería MetabólicaRESUMEN
BACKGROUND: UV-sensitive syndrome (UVSS) is a rare autosomal recessive genodermatosis characterised by photosensitivity, and hyperpigmentation, freckling, and dryness of sun exposed areas. In contrast to other photosensitivity disorders, affected patients show no predisposition to cutaneous melanoma or neurological dysfunction. UVSS results from a defect in the transcription-coupled nucleotide excision repair (TC-NER) mechanism. UVSS can be caused by mutations in the genes ERCC8, ERCC6, and UVSSA. OBJECTIVE: To determine the underlying genetic cause of UVSS and its functional consequences in nine members of two large, unrelated consanguineous pedigrees from Pakistan. METHODS: Genomic DNA from one affected member of each family was subjected to whole exome sequencing. The identified mutation was then validated via Sanger sequencing using samples from all available family members. Molecular cloning and mammalian cell cultures were used for the translation and localisation of wild type (WT) and mutant constructs. RESULTS: A novel homozygous nonsense mutation, (c.1040G>A [p.(Trp347*)]), was detected in exon 6 of the UVSSA gene in both families. Sanger sequencing revealed co-segregation of the nonsense mutation with the UVSS phenotype. Immunoblotting revealed the anticipated 81kDa band for the WT construct, and a truncated protein of around 39kDa for the mutant. In mutant samples, immunofluorescence revealed mislocalisation of UVSSA from the nucleus to the cytoplasm. CONCLUSIONS: This is the first report of UVSS in the Pakistani population and the fourth report of a disease-causing mutation in UVSSA. The study broadens the UVSSA mutational spectrum, and contributes to functional understanding of truncated UVSSA proteins.
Asunto(s)
Proteínas Portadoras/genética , Trastornos por Fotosensibilidad/genética , Adolescente , Niño , Codón sin Sentido , Consanguinidad , Análisis Mutacional de ADN , Femenino , Homocigoto , Humanos , Masculino , Pakistán , Linaje , Secuenciación del ExomaRESUMEN
Inbreeding and enemy infestation are common in plants and can synergistically reduce their performance. This inbreeding ×environment (I × E) interaction may be of particular importance for the success of plant invasions if introduced populations experience a release from attack by natural enemies relative to their native conspecifics. Here, we investigate whether inbreeding affects plant infestation damage, whether inbreeding depression in growth and reproduction is mitigated by enemy release, and whether this effect is more pronounced in invasive than native plant populations. We used the invader Silene latifolia and its natural enemies as a study system. We performed two generations of experimental out- and inbreeding within eight native (European) and eight invasive (North American) populations under controlled conditions using field-collected seeds. Subsequently, we exposed the offspring to an enemy exclusion and inclusion treatment in a common garden in the species' native range to assess the interactive effects of population origin (range), breeding treatment, and enemy treatment on infestation damage, growth, and reproduction. Inbreeding increased flower and leaf infestation damage in plants from both ranges, but had opposing effects on fruit damage in native versus invasive plants. Inbreeding significantly reduced plant fitness; whereby, inbreeding depression in fruit number was higher in enemy inclusions than exclusions. This effect was equally pronounced in populations from both distribution ranges. Moreover, the magnitude of inbreeding depression in fruit number was lower in invasive than native populations. These results support that inbreeding has the potential to reduce plant defenses in S. latifolia, which magnifies inbreeding depression in the presence of enemies. However, future studies are necessary to further explore whether enemy release in the invaded habitat has actually decreased inbreeding depression and thus facilitated the persistence of inbred founder populations and invasion success.
RESUMEN
Hypotrichosis simplex (HS) with and without woolly hair (WH) comprises a group of rare, monogenic disorders of hair loss. Patients present with a diffuse loss of scalp and/or body hair, which usually begins in early childhood and progresses into adulthood. Some of the patients also show hair that is tightly curled. Approximately 10 genes for autosomal recessive and autosomal dominant forms of HS have been identified in the last decade, among them five genes for the dominant form. We collected blood and buccal samples from 17 individuals of a large British family with HS and WH. After having sequenced all known dominant genes for HS in this family without the identification of any disease causing mutation, we performed a genome-wide scan, using the HumanLinkage-24 BeadChip, followed by a classical linkage analysis; and whole exome-sequencing (WES). Evidence for linkage was found for a region on chromosome 4q35.1-q35.2 with a maximum LOD score of 3.61. WES led to the identification of a mutation in the gene SORBS2, encoding sorbin and SH3 domain containing 2. Unfortunately, we could not find an additional mutation in any other patient/family with HS; and in cell culture, we could not observe any difference between cloned wildtype and mutant SORBS2 using western blotting and immunofluorescence analyses. Therefore, at present, SORBS2 cannot be considered a definite disease gene for this phenotype. However, the locus on chromosome 4q is a robust and novel finding for hypotrichosis with woolly hair. Further fine mapping and sequencing efforts are therefore warranted in order to confirm SORBS2 as a plausible HS disease gene.
Asunto(s)
Cromosomas Humanos Par 4 , Genes Dominantes , Predisposición Genética a la Enfermedad , Hipotricosis/diagnóstico , Hipotricosis/genética , Fenotipo , Sitios de Carácter Cuantitativo , Alelos , Mapeo Cromosómico , Femenino , Estudios de Asociación Genética , Ligamiento Genético , Humanos , Masculino , Mutación , Linaje , Reino Unido , Secuenciación Completa del GenomaRESUMEN
Dowling-Degos disease (DDD) is an autosomal-dominant disorder of skin pigmentation associated with mutations in keratin 5 (KRT5), protein O-fucosyltransferase 1 (POFUT1), or protein O-glucosyltransferase 1 (POGLUT1). Here, we have identified 6 heterozygous truncating mutations in PSENEN, encoding presenilin enhancer protein 2, in 6 unrelated patients and families with DDD in whom mutations in KRT5, POFUT1, and POGLUT1 have been excluded. Further examination revealed that the histopathologic feature of follicular hyperkeratosis distinguished these 6 patients from previously studied individuals with DDD. Knockdown of psenen in zebrafish larvae resulted in a phenotype with scattered pigmentation that mimicked human DDD. In the developing zebrafish larvae, in vivo monitoring of pigment cells suggested that disturbances in melanocyte migration and differentiation underlie the DDD pathogenesis associated with PSENEN. Six of the PSENEN mutation carriers presented with comorbid acne inversa (AI), an inflammatory hair follicle disorder, and had a history of nicotine abuse and/or obesity, which are known trigger factors for AI. Previously, PSENEN mutations were identified in familial AI, and comanifestation of DDD and AI has been reported for decades. The present work suggests that PSENEN mutations can indeed cause a comanifestation of DDD and AI that is likely triggered by predisposing factors for AI. Thus, the present report describes a DDD subphenotype in PSENEN mutation carriers that is associated with increased susceptibility to AI.
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Secretasas de la Proteína Precursora del Amiloide/genética , Hidradenitis Supurativa/genética , Hiperpigmentación/genética , Proteínas de la Membrana/genética , Enfermedades Cutáneas Genéticas/genética , Enfermedades Cutáneas Papuloescamosas/genética , Animales , Codón sin Sentido , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Hidradenitis Supurativa/enzimología , Hiperpigmentación/enzimología , Masculino , Enfermedades Cutáneas Genéticas/enzimología , Enfermedades Cutáneas Papuloescamosas/enzimología , Pez CebraRESUMEN
Female pattern hair loss (FPHL) is a common hair loss disorder in women and has a complex mode of inheritance. The etiopathogenesis of FPHL is largely unknown; however, it is hypothesized that FPHL and male pattern baldness [androgenetic alopecia (AGA)] share common genetic susceptibility alleles. Our recent findings indicate that the major AGA locus, an X-chromosome region containing the androgen receptor and the ectodysplasin A2 receptor (EDA2R) genes, may represent a common genetic factor underlying both early-onset FPHL and AGA. This gives further support for the widespread assumption of shared susceptibility loci for FPHL and AGA. However, we could not demonstrate association of further AGA risk loci, including 20p11, 1p36.22, 2q37.3, 7p21.1, 7q11.22, 17q21.31, and 18q21.1, with FPHL. Interestingly, a recent study identified four novel AGA risk loci in chromosomal regions 2q35, 3q25.1, 5q33.3, and 12p12.1. In particular, the 2q35 locus and its gene WNT10A point to an as-yet unknown involvement of the WNT signaling pathway in AGA. We hypothesized that the novel loci and thus also the WNT signaling may have a role in the etiopathogenesis of FPHL and therefore examined the role of these novel AGA risk loci in our FPHL samples comprising 440 German and 145 UK affected patients, 500 German unselected controls (blood donors), and 179 UK supercontrols. Patients and controls were genotyped for the top two single nucleotide polymorphisms at each of the four AGA loci. However, none of the genotyped variants displayed any significant association. In conclusion, the results of this study provide no support for the hypothesis that the novel AGA loci influence susceptibility to FPHL.
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Alopecia/genética , Receptores Androgénicos/genética , Proteínas Wnt/genética , Receptor Xedar/genética , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Vía de Señalización Wnt/genéticaAsunto(s)
Glucosiltransferasas/genética , Hiperpigmentación/genética , Mutación , Enfermedades Cutáneas Genéticas/genética , Enfermedades Cutáneas Papuloescamosas/genética , Análisis Mutacional de ADN , Progresión de la Enfermedad , Femenino , Glucosiltransferasas/metabolismo , Humanos , Hiperpigmentación/metabolismo , Masculino , Transducción de Señal , Enfermedades Cutáneas Genéticas/metabolismo , Enfermedades Cutáneas Papuloescamosas/metabolismoRESUMEN
BACKGROUND: Paediatric reference values for novel markers of phosphate homeostasis, bone formation and resorption and their putative relationship to growth are lacking. METHODS: A total of 424 healthy children, adolescents and young adults (221 males) aged 0.1-21 y, were enrolled in this cross-sectional study. Height, weight and height velocity were assessed. Plasma/serum samples for determination of C-terminal fragment of fibroblast growth factor-23 (cFGF-23), sclerostin, bone alkaline phosphatase (BAP) and tartrate-resistant acid phosphatase 5b (TRAP5b) were available from 222, 264, 352 and 338 individuals, respectively. Calculation of cross-sectional centiles and z-scores was based on median (M), standard coefficient of variation (S) and the Box-Cox power (L) of transformation (LMS method) per age cohort. Correlations between variables as well as with growth were assessed. RESULTS: cFGF-23, BAP and TRAP5b were significantly correlated with age (each P < 0.01), with highest values during infancy and adolescence. Serum levels of BAP and TRAP5b were significantly higher in adolescent boys compared with girls (each P < 0.01). In contrast, sclerostin levels were independent of age and gender. BAP and TRAP5b were strongly correlated and both were significantly associated with cFGF-23 and sclerostin as well (each P < 0.01). cFGF-23 was positively correlated with serum phosphate and renal phosphate threshold concentration (each P < 0.01). Height, weight, body mass index and height velocity were weakly correlated with BAP and TRAP5b (each P < 0.05). CONCLUSIONS: This study provides age- and gender-related centile charts and z-scores for cFGF-23, BAP, TRAP5b and sclerostin and highlights the link between phosphate homeostasis and markers of bone metabolism during growth.