RESUMEN
CONTEXT: Kisspeptin-neurokinin B (NKB)-dynorphin neurons are critical regulators of the hypothalamic-pituitary-gonadal axis. NKB and dynorphin are hypothesized to influence the frequency of GnRH pulses, whereas kisspeptin is hypothesized to be a generator of the GnRH pulse. How these neuropeptides interact remains unclear. OBJECTIVE: To probe the role of NKB in GnRH pulse generation and to determine the interactions between NKB, kisspeptin, and dynorphin in humans and mice with a complete absence of NKB. DESIGN: Case/control. SETTING: Academic medical center. PARTICIPANTS: Members of a consanguineous family bearing biallelic loss-of-function mutations in the gene encoding NKB and NKB-deficient mice. INTERVENTIONS: Frequent blood sampling to characterize neuroendocrine profile and administration of kisspeptin, GnRH, and naloxone, a nonspecific opioid receptor antagonist used to block dynorphin. MAIN OUTCOME MEASURES: LH pulse characteristics. RESULTS: Humans lacking NKB demonstrate slow LH pulse frequency, which can be increased by opioid antagonism. Mice lacking NKB also demonstrate impaired LH secretion, which can be augmented with an identical pharmacologic manipulation. Both mice and humans with NKB deficiency respond to exogenous kisspeptin. CONCLUSION: The preservation of LH pulses in the absence of NKB and dynorphin signaling suggests that both peptides are dispensable for GnRH pulse generation and kisspeptin responsiveness. However, NKB and dynorphin appear to have opposing roles in the modulation of GnRH pulse frequency.
Asunto(s)
Dinorfinas/genética , Hipogonadismo/genética , Kisspeptinas/genética , Hormona Luteinizante/administración & dosificación , Neuroquinina B/genética , Transducción de Señal/efectos de los fármacos , Centros Médicos Académicos , Adolescente , Adulto , Animales , Estudios de Casos y Controles , Niño , Modelos Animales de Enfermedad , Femenino , Hormona Liberadora de Gonadotropina/administración & dosificación , Humanos , Hipogonadismo/sangre , Hipogonadismo/tratamiento farmacológico , Ratones , Ratones Noqueados , Antagonistas de Narcóticos/administración & dosificación , Neuronas/efectos de los fármacos , Sustancia P/metabolismo , Resultado del Tratamiento , Adulto JovenRESUMEN
Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic form of isolated gonadotropin-releasing hormone (GnRH) deficiency caused by mutations in > 30 genes. Fibroblast growth factor receptor 1 (FGFR1) is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH FGFR1 mutation (p.L342S) decreases signaling of the metabolic regulator FGF21 by impairing the association of FGFR1 with ß-Klotho (KLB), the obligate co-receptor for FGF21. We thus hypothesized that the metabolic FGF21/KLB/FGFR1 pathway is involved in CHH Genetic screening of 334 CHH patients identified seven heterozygous loss-of-function KLB mutations in 13 patients (4%). Most patients with KLB mutations (9/13) exhibited metabolic defects. In mice, lack of Klb led to delayed puberty, altered estrous cyclicity, and subfertility due to a hypothalamic defect associated with inability of GnRH neurons to release GnRH in response to FGF21. Peripheral FGF21 administration could indeed reach GnRH neurons through circumventricular organs in the hypothalamus. We conclude that FGF21/KLB/FGFR1 signaling plays an essential role in GnRH biology, potentially linking metabolism with reproduction.
Asunto(s)
Factores de Crecimiento de Fibroblastos/metabolismo , Hormona Liberadora de Gonadotropina/metabolismo , Síndrome de Kallmann/genética , Proteínas de la Membrana/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Animales , Células COS , Caenorhabditis elegans/genética , Chlorocebus aethiops , Estudios de Cohortes , Femenino , Factores de Crecimiento de Fibroblastos/genética , Hormona Liberadora de Gonadotropina/genética , Células HEK293 , Humanos , Hipotálamo/metabolismo , Proteínas Klotho , Masculino , Ratones Endogámicos C57BL , Ratones Mutantes , Neuronas/metabolismo , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genéticaRESUMEN
CONTEXT: Pheochromocytomas and paragangliomas are notable for a high frequency of inherited cases, many of which present as apparently sporadic tumors. OBJECTIVE: The objective of this study was to establish a comprehensive next generation sequencing (NGS)-based strategy for the diagnosis of patients with pheochromocytoma and paraganglioma by testing simultaneously for mutations in MAX, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and VHL. DESIGN: After the methodology for the assay was designed and established, it was validated on DNA samples with known genotype and then patients were studied prospectively. SETTING: The study was performed in a diagnostic genetics laboratory. PATIENTS: DNA samples from 205 individuals affected with adrenal or extraadrenal pheochromocytoma/head and neck paraganglioma (PPGL/HNPGL) were analyzed. A proof-of-principle study was performed using 85 samples known to contain a variant in 1 or more of the genes to be tested, followed by prospective analysis of an additional 120 samples. MAIN OUTCOME MEASURES: We assessed the ability to use an NGS-based method to perform comprehensive analysis of genes implicated in inherited PPGL/HNPGL. RESULTS: The proof-of-principle study showed that the NGS assay and analysis gave a sensitivity of 98.7%. A pathogenic mutation was identified in 16.6% of the prospective analysis cohort of 120 patients. CONCLUSIONS: A comprehensive NGS-based strategy for the analysis of genes associated with predisposition to PPGL and HNPGL was established, validated, and introduced into diagnostic service. The new assay provides simultaneous analysis of 9 genes and allows more rapid and cost-effective mutation detection than the previously used conventional Sanger sequencing-based methodology.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/diagnóstico , Mutación de Línea Germinal , Neoplasias de Cabeza y Cuello/diagnóstico , Paraganglioma/diagnóstico , Feocromocitoma/diagnóstico , Neoplasias de las Glándulas Suprarrenales/economía , Neoplasias de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/metabolismo , Estudios de Cohortes , Ahorro de Costo , Costos y Análisis de Costo , Análisis Mutacional de ADN/economía , Predisposición Genética a la Enfermedad , Pruebas Genéticas/economía , Pruebas Genéticas/métodos , Neoplasias de Cabeza y Cuello/economía , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/metabolismo , Costos de la Atención en Salud , Humanos , Paraganglioma/economía , Paraganglioma/genética , Paraganglioma/metabolismo , Feocromocitoma/economía , Feocromocitoma/genética , Feocromocitoma/metabolismo , Estudios Prospectivos , Subunidades de Proteína/química , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , Proteínas Proto-Oncogénicas c-ret/química , Proteínas Proto-Oncogénicas c-ret/genética , Proteínas Proto-Oncogénicas c-ret/metabolismo , Sensibilidad y Especificidad , Succinato Deshidrogenasa/química , Succinato Deshidrogenasa/genética , Succinato Deshidrogenasa/metabolismo , Reino Unido , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/química , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismoRESUMEN
OBJECTIVES: Research studies have reported that about a third of individuals with phaeochromocytoma/paraganglioma (PPGL) have an inherited predisposition, although the frequency of specific mutations can vary between populations. We evaluated VHL, SDHB and SDHD mutation testing in cohorts of patients with non-syndromic PPGL and head and neck paraganglioma (HNPGL). DESIGN: Prospective, observational evaluation of NHS practice. PATIENTS: Individuals with PPGL/HNPGL referred to a supraregional genetics testing service over a 10-year period. MEASUREMENTS: Clinical (age, tumour site, malignancy, etc.), mutation frequencies and characteristics. RESULTS: A total of 501 probands with PPGL (n = 413) or HNPGL (n = 88) were studied. Thirty-one percent of patients with PPGL presented had a pathogenic mutation in SDHB, SDHD or VHL. Mutation detection rates were highest in those with a positive family history (62%), malignancy (53%), multiple tumours (33%) or PGL (44%). Twenty-eight percent of individuals with a single sporadic phaeochromocytoma had a mutation. Overall, 63% of patients with HNPGL had a mutation (92% of those with a family history, 89% of those with multicentric tumours and 34% of those with a single sporadic HNPGL). Penetrance was calculated in 121 SDHB mutation-positive probands and 187 of their mutation-positive relatives. Most relatives were asymptomatic and lifetime penetrance in non-proband SDHB mutation carriers was <50%. CONCLUSIONS: Practice-based evaluations of genetic testing in PPGL reveal high mutation detection rates. Although clinical criteria can be used to prioritize mutation testing, mutations were detected in 'low risk groups' indicating a need for comprehensive and inexpensive genetic testing strategies for PPGL and HNPGL.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/genética , Predisposición Genética a la Enfermedad/genética , Neoplasias de Cabeza y Cuello/genética , Paraganglioma/genética , Feocromocitoma/genética , Succinato Deshidrogenasa/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Pruebas Genéticas , Humanos , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. Pseudohypoaldosteronism type II (PHAII), a rare Mendelian syndrome featuring hypertension, hyperkalaemia and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption and K(+) and H(+) excretion. Here we used exome sequencing to identify mutations in kelch-like 3 (KLHL3) or cullin 3 (CUL3) in PHAII patients from 41 unrelated families. KLHL3 mutations are either recessive or dominant, whereas CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-domain-containing kelch proteins such as KLHL3 are components of cullin-RING E3 ligase complexes that ubiquitinate substrates bound to kelch propeller domains. Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrate and cullin binding, respectively. Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion. Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates. Disease features are reversed by thiazide diuretics, which inhibit the Na-Cl cotransporter in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3 and CUL3 mutations, increased Na-Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite the combined complexities of locus heterogeneity, mixed models of transmission and frequent de novo mutation, and establish a fundamental role for KLHL3 and CUL3 in blood pressure, K(+) and pH homeostasis.
Asunto(s)
Proteínas Portadoras/genética , Proteínas Cullin/genética , Hipertensión/genética , Mutación/genética , Seudohipoaldosteronismo/genética , Desequilibrio Hidroelectrolítico/genética , Proteínas Adaptadoras Transductoras de Señales , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Presión Sanguínea/genética , Proteínas Portadoras/química , Estudios de Cohortes , Proteínas Cullin/química , Electrólitos , Exones/genética , Femenino , Perfilación de la Expresión Génica , Genes Dominantes/genética , Genes Recesivos/genética , Genotipo , Homeostasis/genética , Humanos , Concentración de Iones de Hidrógeno , Hipertensión/complicaciones , Hipertensión/fisiopatología , Masculino , Ratones , Proteínas de Microfilamentos , Modelos Moleculares , Datos de Secuencia Molecular , Fenotipo , Potasio/metabolismo , Seudohipoaldosteronismo/complicaciones , Seudohipoaldosteronismo/fisiopatología , Cloruro de Sodio/metabolismo , Desequilibrio Hidroelectrolítico/complicaciones , Desequilibrio Hidroelectrolítico/fisiopatologíaRESUMEN
CONTEXT: P450 oxidoreductase deficiency (PORD) is a unique congenital adrenal hyperplasia variant that manifests with glucocorticoid deficiency, disordered sex development (DSD), and skeletal malformations. No comprehensive data on genotype-phenotype correlations in Caucasian patients are available. OBJECTIVE: The objective of the study was to establish genotype-phenotype correlations in a large PORD cohort. DESIGN: The design of the study was the clinical, biochemical, and genetic assessment including multiplex ligation-dependent probe amplification (MLPA) in 30 PORD patients from 11 countries. RESULTS: We identified 23 P450 oxidoreductase (POR) mutations (14 novel) including an exonic deletion and a partial duplication detected by MLPA. Only 22% of unrelated patients carried homozygous POR mutations. p.A287P was the most common mutation (43% of unrelated alleles); no other hot spot was identified. Urinary steroid profiling showed characteristic PORD metabolomes with variable impairment of 17α-hydroxylase and 21-hydroxylase. Short cosyntropin testing revealed adrenal insufficiency in 89%. DSD was present in 15 of 18 46,XX and seven of 12 46,XY individuals. Homozygosity for p.A287P was invariably associated with 46,XX DSD but normal genitalia in 46,XY individuals. The majority of patients with mild to moderate skeletal malformations, assessed by a novel scoring system, were compound heterozygous for missense mutations, whereas nearly all patients with severe malformations carried a major loss-of-function defect on one of the affected alleles. CONCLUSIONS: We report clinical, biochemical, and genetic findings in a large PORD cohort and show that MLPA is a useful addition to POR mutation analysis. Homozygosity for the most frequent mutation in Caucasians, p.A287P, allows for prediction of genital phenotype and moderate malformations. Adrenal insufficiency is frequent, easily overlooked, but readily detected by cosyntropin testing.
Asunto(s)
Hiperplasia Suprarrenal Congénita/genética , NADPH-Ferrihemoproteína Reductasa/genética , Adolescente , Hiperplasia Suprarrenal Congénita/orina , Insuficiencia Suprarrenal/genética , Insuficiencia Suprarrenal/metabolismo , Insuficiencia Suprarrenal/orina , Adulto , Niño , Estudios de Cohortes , Análisis Mutacional de ADN/métodos , Trastornos del Desarrollo Sexual , Femenino , Estudios de Asociación Genética , Genitales/anomalías , Hormonas Esteroides Gonadales/orina , Humanos , Masculino , Metaboloma , Modelos Biológicos , Modelos Moleculares , Reacción en Cadena de la Polimerasa Multiplex/métodos , NADPH-Ferrihemoproteína Reductasa/deficiencia , NADPH-Ferrihemoproteína Reductasa/fisiología , Adulto JovenRESUMEN
Marshall-Smith syndrome (MSS) is a distinctive entity of unknown etiology with fewer than 50 patients described in the medical literature to date. Through an International collaboration and use of an online wiki to facilitate data collection and sharing, we further delineate the phenotype and natural history of this syndrome. We present 15 new patients, the oldest being 30 years, provide an update on four previously published cases, and compare all patients with other patients reported in literature. Main clinical features are moderate to severe developmental delay with absent or limited speech, unusual behavior, dysharmonic bone maturation, respiratory compromise secondary to upper airway obstruction, short stature, and kyphoscoliosis. Facial features are characteristic with high forehead, underdeveloped midface, proptosis, anteverted nares, and everted lips. Minor abnormalities of brain morphology such as hypoplasia of the corpus callosum are common. Mortality from respiratory complications is high, but airway support increasingly allows survival into adulthood. Array-CGH was performed on 12 of the cohort and no copy number variants of clear clinical relevance were identified. The present study is the first reported use of an online wiki to aid delineation of a genetic syndrome, and illustrates its value in collecting detailed data in rare conditions.
Asunto(s)
Anomalías Múltiples , Enfermedades del Desarrollo Óseo , Anomalías Craneofaciales , Displasia Septo-Óptica , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Adolescente , Adulto , Enfermedades del Desarrollo Óseo/genética , Enfermedades del Desarrollo Óseo/patología , Niño , Preescolar , Hibridación Genómica Comparativa , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/patología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Fenotipo , Displasia Septo-Óptica/genética , Displasia Septo-Óptica/patología , Factores de Tiempo , Adulto JovenRESUMEN
CONTEXT: Mutations in TAC3 and TACR3 (encoding neurokinin B and its receptor) have been identified in Turkish patients with idiopathic hypogonadotropic hypogonadism (IHH), but broader populations have not yet been tested and genotype-phenotype correlations have not been established. OBJECTIVE: A broad cohort of normosmic IHH probands was screened for mutations in TAC3/TACR3 to evaluate the prevalence of such mutations and define the genotype/phenotype relationships. DESIGN AND SETTING: The study consisted of sequencing of TAC3/TACR3, in vitro functional assays, and neuroendocrine phenotyping conducted in tertiary care centers worldwide. PATIENTS OR OTHER PARTICIPANTS: 345 probands, 18 family members, and 292 controls were studied. INTERVENTION: Reproductive phenotypes throughout reproductive life and before and after therapy were examined. MAIN OUTCOME MEASURE: Rare sequence variants in TAC3/TACR3 were detected. RESULTS: In TACR3, 19 probands harbored 13 distinct coding sequence rare nucleotide variants [three nonsense mutations, six nonsynonymous, four synonymous (one predicted to affect splicing)]. In TAC3, one homozygous single base pair deletion was identified, resulting in complete loss of the neurokinin B decapeptide. Phenotypic information was available on 16 males and seven females with coding sequence variants in TACR3/TAC3. Of the 16 males, 15 had microphallus; none of the females had spontaneous thelarche. Seven of the 16 males and five of the seven females were assessed after discontinuation of therapy; six of the seven males and four of the five females demonstrated evidence for reversibility of their hypogonadotropism. CONCLUSIONS: Mutations in the neurokinin B pathway are relatively common as causes of hypogonadism. Although the neurokinin B pathway appears essential during early sexual development, its importance in sustaining the integrity of the hypothalamic-pituitary-gonadal axis appears attenuated over time.
Asunto(s)
Hormona Liberadora de Gonadotropina/metabolismo , Neuroquinina B/genética , Neuroquinina B/farmacología , Receptores de Neuroquinina-3/genética , Receptores de Taquicininas/genética , Taquicininas/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Animales , Células COS , Chlorocebus aethiops , Codón sin Sentido/genética , Análisis Mutacional de ADN , Etnicidad , Femenino , Fertilidad/genética , Variación Genética , Humanos , Recién Nacido , Masculino , Datos de Secuencia Molecular , Mutación/fisiología , Linaje , Pubertad/fisiología , Caracteres Sexuales , Transfección , Adulto JovenRESUMEN
CONTEXT: Steroid 11beta-hydroxylase (CYP11B1) deficiency (11OHD) is the second most common form of congenital adrenal hyperplasia (CAH). Cases of nonclassic 11OHD are rare compared with the incidence of nonclassic 21-hydroxylase deficiency. OBJECTIVE: The aim of the study was to analyze the functional consequences of seven novel CYP11B1 mutations (p.M88I, p.W116G, p.P159L, p.A165D, p.K254_A259del, p.R366C, p.T401A) found in three patients with classic 11OHD, two patients with nonclassic 11OHD, and three heterozygous carriers for CYP11B1 mutations. METHODS: We conducted functional studies employing a COS7 cell in vitro expression system comparing wild-type (WT) and mutant CYP11B1 activity. Mutants were examined in a computational three-dimensional model of the CYP11B1 protein. RESULTS: All mutations (p.W116G, p.A165D, p.K254_A259del) found in patients with classic 11OHD have absent or very little 11beta-hydroxylase activity relative to WT. The mutations detected in patients with nonclassic 11OHD showed partial functional impairment, with one patient being homozygous (p.P159L; 25% of WT) and the other patient compound heterozygous for a novel mild p.M88I (40% of WT) and the known severe p.R383Q mutation. The two mutations detected in heterozygous carriers (p.R366C, p.T401A) also reduced CYP11B1 activity by 23 to 37%, respectively. CONCLUSION: Functional analysis results allow for the classification of novel CYP11B1 mutations as causative for classic and nonclassic 11OHD, respectively. Four partially inactivating mutations are predicted to result in nonclassic 11OHD. These findings double the number of mild CYP11B1 mutations previously described as associated with mild 11OHD. Our data are important to predict phenotypic expression and provide important information for clinical and genetic counseling in 11OHD.
Asunto(s)
Hiperplasia Suprarrenal Congénita/genética , Mutación , Esteroide 11-beta-Hidroxilasa/genética , Adolescente , Adulto , Animales , Células COS , Niño , Chlorocebus aethiops , Femenino , Heterocigoto , Humanos , Masculino , Modelos Moleculares , Esteroide 11-beta-Hidroxilasa/química , Esteroide 11-beta-Hidroxilasa/fisiologíaRESUMEN
Succinate dehydrogenase B (SDHB) and D (SDHD) subunit gene mutations predispose to adrenal and extraadrenal pheochromocytomas, head and neck paragangliomas (HNPGL), and other tumor types. We report tumor risks in 358 patients with SDHB (n=295) and SDHD (n=63) mutations. Risks of HNPGL and pheochromocytoma in SDHB mutation carriers were 29% and 52%, respectively, at age 60 years and 71% and 29%, respectively, in SDHD mutation carriers. Risks of malignant pheochromocytoma and renal tumors (14% at age 70 years) were higher in SDHB mutation carriers; 55 different mutations (including a novel recurrent exon 1 deletion) were identified. No clear genotype-phenotype correlations were detected for SDHB mutations. However, SDHD mutations predicted to result in loss of expression or a truncated or unstable protein were associated with a significantly increased risk of pheochromocytoma compared to missense mutations that were not predicted to impair protein stability (most such cases had the common p.Pro81Leu mutation). Analysis of the largest cohort of SDHB/D mutation carriers has enhanced estimates of penetrance and tumor risk and supports in silicon protein structure prediction analysis for functional assessment of mutations. The differing effect of the SDHD p.Pro81Leu on HNPGL and pheochromocytoma risks suggests differing mechanisms of tumorigenesis in SDH-associated HNPGL and pheochromocytoma.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/genética , Mutación de Línea Germinal , Paraganglioma/genética , Feocromocitoma/genética , Succinato Deshidrogenasa/genética , Adolescente , Neoplasias de las Glándulas Suprarrenales/patología , Adulto , Anciano , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Persona de Mediana Edad , Paraganglioma/patología , Fenotipo , Feocromocitoma/patología , Adulto JovenAsunto(s)
Enfermedades en Gemelos/diagnóstico , Ependimoma/patología , Neurofibromatosis 2/diagnóstico , Neuroma Acústico/patología , Neoplasias de la Columna Vertebral/patología , Gemelos Monocigóticos , Niño , Enfermedades en Gemelos/genética , Humanos , Imagen por Resonancia Magnética , Masculino , Neurofibromatosis 2/genéticaRESUMEN
Until recently, the PMS2 DNA mismatch repair gene has only rarely been implicated as a cancer susceptibility locus. New studies have shown, however, that earlier analyses of this gene have had technical limitations and also that the genetic behavior of mutant PMS2 alleles is unusual, in that, unlike MLH1 or MSH2 mutations, PMS2 mutations show low heterozygote penetrance. As a result, a dominantly inherited cancer predisposition has not been a feature reported in families with PMS2 mutations. Such families have instead been ascertained through childhood-onset cancers in homozygotes or through apparently sporadic colorectal cancer in heterozygotes. We present further information on the phenotype associated with homozygous PMS2 deficiency in 13 patients from six families of Pakistani origin living in the United Kingdom. This syndrome is characterized by café-au-lait skin pigmentation and a characteristic tumor spectrum, including leukemias, lymphomas, cerebral malignancies (such as supratentorial primitive neuroectodermal tumors, astrocytomas, and glioblastomas), and colorectal neoplasia with an onset in early adult life. We present evidence for a founder effect in five families, all of which carried the same R802-->X mutation (i.e., arginine-802 to stop) in PMS2. This cancer syndrome can be mistaken for neurofibromatosis type 1, with important management implications including the risk of the disorder occurring in siblings and the likelihood of tumor development in affected individuals.
Asunto(s)
Adenosina Trifosfatasas/genética , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Efecto Fundador , Mutación , Neoplasias/genética , Adolescente , Arginina , Astrocitoma/genética , Manchas Café con Leche/genética , Niño , Pólipos del Colon/genética , Reparación del ADN , Femenino , Predisposición Genética a la Enfermedad , Glioma/genética , Humanos , Leucemia de Células T/genética , Linfoma de Células B/genética , Linfoma de Células T/genética , Masculino , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto , Neoplasias/epidemiología , Neoplasias Primarias Secundarias/genética , Pakistán/etnología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Reino Unido/epidemiologíaRESUMEN
We identified 266 individuals with intragenic NSD1 mutations or 5q35 microdeletions encompassing NSD1 (referred to as "NSD1-positive individuals"), through analyses of 530 subjects with diverse phenotypes. Truncating NSD1 mutations occurred throughout the gene, but pathogenic missense mutations occurred only in functional domains (P < 2 x 10(-16)). Sotos syndrome was clinically diagnosed in 99% of NSD1-positive individuals, independent of the molecular analyses, indicating that NSD1 aberrations are essentially specific to this condition. Furthermore, our data suggest that 93% of patients who have been clinically diagnosed with Sotos syndrome have identifiable NSD1 abnormalities, of which 83% are intragenic mutations and 10% are 5q35 microdeletions. We reviewed the clinical phenotypes of 239 NSD1-positive individuals. Facial dysmorphism, learning disability, and childhood overgrowth were present in 90% of the individuals. However, both the height and head circumference of 10% of the individuals were within the normal range, indicating that overgrowth is not obligatory for the diagnosis of Sotos syndrome. A broad spectrum of associated clinical features was also present, the occurrence of which was largely independent of genotype, since individuals with identical mutations had different phenotypes. We compared the phenotypes of patients with intragenic NSD1 mutations with those of patients with 5q35 microdeletions. Patients with microdeletions had less-prominent overgrowth (P = .0003) and more-severe learning disability (P = 3 x 10(-9)) than patients with mutations. However, all features present in patients with microdeletions were also observed in patients with mutations, and there was no correlation between deletion size and the clinical phenotype, suggesting that the deletion of additional genes in patients with 5q35 microdeletions has little specific effect on phenotype. We identified only 13 familial cases. The reasons for the low vertical transmission rate are unclear, although familial cases were more likely than nonfamilial cases (P = .005) to carry missense mutations, suggesting that the underlying NSD1 mutational mechanism in Sotos syndrome may influence reproductive fitness.
Asunto(s)
Trastornos del Crecimiento/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Discapacidades para el Aprendizaje/genética , Proteínas Nucleares/genética , Secuencia de Aminoácidos , Cromosomas Humanos Par 5/genética , Exones , Facies , Femenino , Mutación del Sistema de Lectura , Eliminación de Gen , Genotipo , Trastornos del Crecimiento/patología , Histona Metiltransferasas , N-Metiltransferasa de Histona-Lisina , Homocigoto , Humanos , Discapacidades para el Aprendizaje/patología , Masculino , Datos de Secuencia Molecular , Mutación , Mutación Missense , Fenotipo , Polimorfismo Genético , Pronóstico , Homología de Secuencia de Aminoácido , Síndrome , Dedos de ZincRESUMEN
Warburg Micro syndrome (WARBM1) is a severe autosomal recessive disorder characterized by developmental abnormalities of the eye and central nervous system and by microgenitalia. We identified homozygous inactivating mutations in RAB3GAP, encoding RAB3 GTPase activating protein, a key regulator of the Rab3 pathway implicated in exocytic release of neurotransmitters and hormones, in 12 families with Micro syndrome. We hypothesize that the underlying pathogenesis of Micro syndrome is a failure of exocytic release of ocular and neurodevelopmental trophic factors.
Asunto(s)
Mutación , Proteínas de Unión al GTP rab/metabolismo , Dominio Catalítico , Sistema Nervioso Central/anomalías , Anomalías del Ojo/patología , Genitales/anomalías , Humanos , Datos de Secuencia Molecular , Síndrome , Proteínas de Unión al GTP rab/genéticaRESUMEN
Sotos syndrome is an overgrowth condition predominantly caused by truncating mutations, missense mutations restricted to functional domains, or deletions of NSD1. NSD1 is a member of a protein family that includes NSD2 and NSD3, both of which show 70-75% sequence identity with NSD1. This strong sequence similarity suggests that abrogation of NSD2 or NSD3 function may cause non-NSD1 Sotos cases or other overgrowth phenotypes. To evaluate this hypothesis, we mutationally screened NSD2 and NSD3 in 78 overgrowth syndrome cases in which NSD1 mutations and deletions had been excluded. Additionally, we used microsatellite markers within the vicinity of the genes to look for whole gene deletions. No truncating mutations or gene deletions were identified in either gene. We identified two conservative missense NSD2 alterations in two non-Sotos overgrowth cases but neither was within a functional domain. We identified three synonymous and two intronic variants in NSD2 and two synonymous base substitutions in NSD3. Our results suggest that despite strong sequence similarity between NSD1, NSD2 and NSD3, the latter genes are unlikely to be making a substantial contribution to overgrowth phenotypes and thus may operate in distinct functional pathways from NSD1.
Asunto(s)
Proteínas Portadoras/genética , Gigantismo/genética , Proteínas Nucleares/genética , Proteínas Represoras/genética , Estudios de Casos y Controles , Femenino , Histona Metiltransferasas , N-Metiltransferasa de Histona-Lisina , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Masculino , Eliminación de Secuencia/genética , Homología de SecuenciaRESUMEN
Sotos syndrome is a childhood overgrowth syndrome characterized by a distinctive facial appearance, height and head circumference >97th percentile, advanced bone age, and developmental delay. Weaver syndrome is characterized by the same criteria but has its own distinctive facial gestalt. Recently, a 2.2-Mb chromosome 5q35 microdeletion, encompassing NSD1, was reported as the major cause of Sotos syndrome, with intragenic NSD1 mutations identified in a minority of cases. We evaluated 75 patients with childhood overgrowth, for intragenic mutations and large deletions of NSD1. The series was phenotypically scored into four groups, prior to the molecular analyses: the phenotype in group 1 (n=37) was typical of Sotos syndrome; the phenotype in group 2 (n=13) was Sotos-like but with some atypical features; patients in group 3 (n=7) had Weaver syndrome, and patients in group 4 (n=18) had an overgrowth condition that was neither Sotos nor Weaver syndrome. We detected three deletions and 32 mutations (13 frameshift, 8 nonsense, 2 splice-site, and 9 missense) that are likely to impair NSD1 functions. The truncating mutations were spread throughout NSD1, but there was evidence of clustering of missense mutations in highly conserved functional domains between exons 13 and 23. There was a strong correlation between presence of an NSD1 alteration and clinical phenotype, in that 28 of 37 (76%) patients in group 1 had NSD1 mutations or deletions, whereas none of the patients in group 4 had abnormalities of NSD1. Three patients with Weaver syndrome had NSD1 mutations, all between amino acids 2142 and 2184. We conclude that intragenic mutations of NSD1 are the major cause of Sotos syndrome and account for some Weaver syndrome cases but rarely occur in other childhood overgrowth phenotypes.
Asunto(s)
Anomalías Múltiples/genética , Proteínas Portadoras/genética , Anomalías Craneofaciales/genética , Trastornos del Crecimiento/genética , Péptidos y Proteínas de Señalización Intracelular , Mutación/genética , Proteínas Nucleares/genética , Secuencia de Aminoácidos , Proteínas Portadoras/química , Niño , Deleción Cromosómica , Cromosomas Humanos Par 5/genética , Análisis Mutacional de ADN , Discapacidades del Desarrollo/genética , Exones/genética , Femenino , Histona Metiltransferasas , N-Metiltransferasa de Histona-Lisina , Humanos , Intrones/genética , Masculino , Datos de Secuencia Molecular , Proteínas Nucleares/química , Linaje , Fenotipo , Polimorfismo Genético/genética , Estructura Terciaria de Proteína , Eliminación de Secuencia/genética , SíndromeRESUMEN
BACKGROUND: Renal tract malformations are, on occasion, associated with uterine malformations. The transcription factor hepatocyte nuclear factor (HNF)-1beta is expressed from the earliest stages of development of the Wolffian duct, the mesonephros and metanephros, and the Müllerian ducts in the mouse. In adult mice HNF-1beta is expressed in the kidney tubules, collecting ducts, and in the oviducts and uterus in the female (Müllerian duct derivatives) and in the epididymis, vas deferens and seminal vesicles (Wolffian duct derivatives) in the male. HNF-1beta mutations have been reported in two families where affected members have renal abnormalities, female genital tract malformations and early-onset diabetes. Renal and uterine abnormalities have not been described in families without early-onset diabetes. METHODS: We sequenced the HNF-1beta gene in nine subjects with renal abnormalities and a personal or family history of female genital tract malformations, but no history of diabetes. RESULTS: Two families were identified with novel HNF-1beta mutations: a missense mutation in exon 2 with conversion of serine to proline at codon 151 (S151P) and a frameshift mutation in exon 3 with a 1 base pair deletion at codon 243 (Q243fsdelC). The S151P mutation proband has cystic kidneys and uterus didelphys. Her affected second son has renal cysts and hypospadias. The Q243fsdelC proband has a single functioning kidney and her two children have renal dysplasia. Histology in one child shows cystic dysplasia with a lack of glomeruli. The proband's sister is a mutation carrier and has a bicornuate uterus. Diabetes is not a feature in either family. CONCLUSIONS: This study confirms an association between HNF-1beta mutations and renal and Müllerian anomalies. The hypospadias may be coincidental. This study describes the first HNF-1beta mutations that are associated with a single functioning kidney and the absence of diabetes. This study further reinforces the variability of the renal and non-renal phenotypes associated with HNF-1beta mutations.