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Telomere maintenance 2 (TELO2), Tel2 interacting protein 2 (TTI2), and Tel2 interacting protein 1 (TTI1) are the three components of the conserved Triple T (TTT) complex that modulates activity of phosphatidylinositol 3-kinase-related protein kinases (PIKKs), including mTOR, ATM, and ATR, by regulating the assembly of mTOR complex 1 (mTORC1). The TTT complex is essential for the expression, maturation, and stability of ATM and ATR in response to DNA damage. TELO2- and TTI2-related bi-allelic autosomal-recessive (AR) encephalopathies have been described in individuals with moderate to severe intellectual disability (ID), short stature, postnatal microcephaly, and a movement disorder (in the case of variants within TELO2). We present clinical, genomic, and functional data from 11 individuals in 9 unrelated families with bi-allelic variants in TTI1. All present with ID, and most with microcephaly, short stature, and a movement disorder. Functional studies performed in HEK293T cell lines and fibroblasts and lymphoblastoid cells derived from 4 unrelated individuals showed impairment of the TTT complex and of mTOR pathway activity which is improved by treatment with Rapamycin. Our data delineate a TTI1-related neurodevelopmental disorder and expand the group of disorders related to the TTT complex.
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Microcefalia , Transtornos dos Movimentos , Transtornos do Neurodesenvolvimento , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Células HEK293 , Serina-Treonina Quinases TORRESUMO
Neurodevelopmental disorders (NDDs) are clinically and genetically heterogenous; many such disorders are secondary to perturbation in brain development and/or function. The prevalence of NDDs is > 3%, resulting in significant sociocultural and economic challenges to society. With recent advances in family-based genomics, rare-variant analyses, and further exploration of the Clan Genomics hypothesis, there has been a logarithmic explosion in neurogenetic "disease-associated genes" molecular etiology and biology of NDDs; however, the majority of NDDs remain molecularly undiagnosed. We applied genome-wide screening technologies, including exome sequencing (ES) and whole-genome sequencing (WGS), to identify the molecular etiology of 234 newly enrolled subjects and 20 previously unsolved Turkish NDD families. In 176 of the 234 studied families (75.2%), a plausible and genetically parsimonious molecular etiology was identified. Out of 176 solved families, deleterious variants were identified in 218 distinct genes, further documenting the enormous genetic heterogeneity and diverse perturbations in human biology underlying NDDs. We propose 86 candidate disease-trait-associated genes for an NDD phenotype. Importantly, on the basis of objective and internally established variant prioritization criteria, we identified 51 families (51/176 = 28.9%) with multilocus pathogenic variation (MPV), mostly driven by runs of homozygosity (ROHs) - reflecting genomic segments/haplotypes that are identical-by-descent. Furthermore, with the use of additional bioinformatic tools and expansion of ES to additional family members, we established a molecular diagnosis in 5 out of 20 families (25%) who remained undiagnosed in our previously studied NDD cohort emanating from Turkey.
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Genômica/métodos , Mutação , Transtornos do Neurodesenvolvimento/epidemiologia , Fenótipo , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Linhagem , Prevalência , Turquia/epidemiologia , Sequenciamento do Exoma , Adulto JovemRESUMO
OBJECTIVES: Carvajal syndrome is a very rare autosomal recessive cardiocutaneous disorder caused by a desmosomal mutation in exon 24 of the desmoplakin gene. It manifests with woolly hair, epidermolytic palmoplantar keratoderma, and arrhythmogenic right ventricular cardiomyopathy. We herein present a patient with heart failure and dilated cardiomyopathy who was diagnosed with Carvajal syndrome because of dermatologic manifestations. CASE PRESENTATION: A seven-year-old girl was referred to our clinic due to decompensated heart failure and clinical deterioration. The patient had severe weakness, tachycardia, and tachypnea. She had a complaint of getting tired quickly for three weeks, and she had shortness of breath and abdominal pain for the last two days. She had hepatomegaly and woolly hair. Mild keratoderma was present on the soles of her feet. Echocardiography demonstrated biventricular dilatation, significantly impaired left ventricular systolic function (ejection fraction 22%), and moderate to severe mitral and tricuspid regurgitation. Molecular genetic evaluation was performed because of cutaneous and cardiac findings, which demonstrated a desmoplakin gene mutation. Homozygous mutation c.4297C > T (p.Gln1433*) was identified in desmoplakin gene, and the diagnosis of Carvajal syndrome was confirmed. CONCLUSIONS: Syndromic types of arrhythmogenic right ventricular cardiomyopathy such as Carvajal syndrome are rare diseases. Awareness about cutaneous manifestations and genetic evaluation would help diagnosis and prevention of sudden death. Genetic counselling is needed in familial cases.
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PURPOSE: Pathogenic variants in genes encoding ubiquitin E3 ligases are known to cause neurodevelopmental syndromes. Additional neurodevelopmental disorders associated with the other genes encoding E3 ligases are yet to be identified. METHODS: Chromosomal analysis and exome sequencing were used to identify the genetic causes in 10 patients from 7 unrelated families with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes. RESULTS: In total, 4 patients were found to have 3 different homozygous loss-of-function (LoF) variants, and 3 patients had 4 compound heterozygous missense variants in the candidate E3 ligase gene, HECTD4, that were rare, absent from controls as homozygous, and predicted to be deleterious in silico. In 3 patients from 2 families with Angelman-like syndrome, paralog-directed candidate gene approach detected 2 LoF variants in the other candidate E3 ligase gene, UBE3C, a paralog of the Angelman syndrome E3 ligase gene, UBE3A. The RNA studies in 4 patients with LoF variants in HECTD4 and UBE3C provided evidence for the LoF effect. CONCLUSION: HECTD4 and UBE3C are novel biallelic rare disease genes, expand the association of the other HECT E3 ligase group with neurodevelopmental syndromes, and could explain some of the missing heritability in patients with a suggestive clinical diagnosis of Angelman syndrome.
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Síndrome de Angelman , Transtornos do Neurodesenvolvimento , Humanos , Síndrome de Angelman/genética , Ubiquitina/genética , Ubiquitina-Proteína Ligases/genética , Transtornos do Neurodesenvolvimento/genética , FenótipoRESUMO
Thrombotic and microangiopathic effects have been reported in COVID-19 patients. This study examined the contribution of the hereditary thrombophilia factors Prothrombin (FII) and Factor V Leiden (FVL) genotypes to the severity of COVID-19 disease and the development of thrombosis. This study investigated FII and FVL alleles in a cohort of 9508 patients (2606 male and 6902 female) with thrombophilia. It was observed that 930 of these patients had been infected by SARS-CoV-2 causing COVID-19. The demographic characteristics of the patients and their COVID-19 medical history were recorded. Detailed clinical manifestations were analyzed in a group of cases (n = 4092). This subgroup was age and gender-matched. FII and FVL frequency data of healthy populations without thrombophilia risk were obtained from Bursa Uludag University Medical Genetic Department's Exome Databank. The ratio of males (31.08%; 27.01%) and the mean age (36.85 ± 15.20; 33.89 ± 14.14) were higher among COVID-19 patients compared to non-COVID-19 patients. The prevalence of FVL and computerized tomography (CT) positivity in COVID-19 patients was statistically significant in the thrombotic subgroup (p < 0.05). FVL prevalence, CT positivity rate, history of thrombosis, and pulmonary thromboembolism complication were found to be higher in deceased COVID-19 patients (p < 0.05). Disease severity was mainly affected by FVL and not related to genotypes at the Prothrombin mutations. Overall, disease severity and development of thrombosis in COVID-19 are mainly affected by the variation within the FVL gene. Possible FVL mutation should be investigated in COVID-19 patients and appropriate treatment should be started earlier in FVL-positive patients.
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COVID-19 , Trombofilia , Trombose , Humanos , Masculino , Feminino , Protrombina/genética , Fatores de Risco , SARS-CoV-2 , Genótipo , Fator V/genética , Trombofilia/epidemiologia , Trombofilia/genética , Gravidade do Paciente , MutaçãoRESUMO
Schaaf-Yang syndrome (SHFYNG) is a rare pleiotropic disorder, characterized by hypotonia, joint contractures, autism spectrum disorders (ASD), and developmental delay/intellectual disability. Although it shares some common features with Prader-Willi Syndrome, joint contractures, and ASD were more commonly detected in in this syndrome. Recently, it was shown that truncating variants in the paternal allele of the MAGEL2 gene cause SHFYNG. Here, we present two patients diagnosed with SHFYNG syndrome having two different novel truncating variants in the MAGEL2 gene, one paternally inherited and one de novo. One patient had obesity, brachydactyly and dysmorphic features, and the other patient presented with contractures, severe hypotonia and early death. This is the first report of Turkish SHFYNG syndrome cases presented to emphasize the phenotypic diversity of the syndrome.
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Contratura , Deficiência Intelectual , Síndrome de Prader-Willi , Humanos , Hipotonia Muscular , Síndrome de Prader-Willi/diagnóstico , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/patologia , Deficiência Intelectual/genética , ProteínasRESUMO
Heterogeneity in symptoms associated with COVID-19 in infected patients remains unclear. ACE2 and TMPRSS2 gene variants are considered possible risk factors for COVID-19. In this study, a retrospective comparative genome analysis of the ACE2 and TMPRSS2 variants from 946 whole-exome sequencing data was conducted. Allele frequencies of all variants were calculated and filtered to remove variants with allele frequencies lower than 0.003 and to prioritize functional coding variants. The majority of detected variants were intronic, only two ACE2 and three TMPRSS2 nonsynonymous variants were detected in the analyzed cohort. The main ACE2 variants that putatively have a protective or susceptibility effect on SARS-CoV-2 have not yet been determined in the Turkish population. The Turkish genetic makeup likely lacks any ACE2 variant that increases susceptibility to SARS-CoV-2 infection. TMPRSS2 rs75603675 and rs12329760 variants that were previously defined as common variants that have different allele frequencies among populations and may have a role in SARS-CoV-2 attachment to host cells were determined in the population. Overall, these data will contribute to the formation of a national variation database and may also contribute to further studies of ACE2 and TMPRSS2 in the Turkish population and differences in SARS-CoV-2 infection among other populations.
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Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19 , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2/genética , COVID-19/epidemiologia , COVID-19/genética , Humanos , Peptidil Dipeptidase A/genética , Estudos Retrospectivos , Fatores de Risco , SARS-CoV-2/genética , Serina Endopeptidases/genética , Sequenciamento do ExomaRESUMO
PURPOSE: Premature ovarian insufficiency (POI) is a heterogeneous disorder characterized by the cessation of menstrual cycles before the age of 40 years due to the depletion or dysfunction of the ovarian follicles. POI is a highly heterogeneous disease in terms of etiology. The aim of this study is to reveal the genetic etiology in POI patients. METHODS: A total of 35 patients (mean age: 27.2 years) from 28 different families diagnosed with POI were included in the study. Karyotype, FMR1 premutation analysis, single nucleotide polymorphism (SNP) array, and whole-exome sequencing (WES) were conducted to determine the genetic etiology of patients. RESULTS: A total of 35 patients with POI were first evaluated by karyotype analysis, and chromosomal anomaly was detected in three (8.5%) and FMR1 premutation was detected in six patients (17%) from two different families. A total of 29 patients without FMR1 premutation were included in the SNP array analysis, and one patient had a 337-kb deletion in the chromosome 6q26 region including PARK2 gene, which was thought to be associated with POI. Twenty-nine cases included in SNP array analysis were evaluated simultaneously with WES analysis, and genetic variant was detected in 55.1% (16/29). CONCLUSION: In the present study, rare novel variants were identified in genes known to be associated with POI, which contribute to the mutation spectrum. The effects of detected novel genes and variations on different pathways such as gonadal development, meiosis and DNA repair, or metabolism need to be investigated by experimental studies. Molecular etiology allows accurate genetic counseling to the patient and family as well as fertility planning.
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Insuficiência Ovariana Primária , Adulto , Aberrações Cromossômicas , Feminino , Proteína do X Frágil da Deficiência Intelectual/genética , Humanos , Cariotipagem , Mutação/genética , Insuficiência Ovariana Primária/diagnóstico , Insuficiência Ovariana Primária/genética , Sequenciamento do ExomaRESUMO
CES (Clinical Exome Sequencing) is a method that we use to diagnose rare diseases with nonspesific clinical features. Besides primary indication for testing genetic information may be detected about diseases which have not yet emerged. ACMG guidelines recommend to report pathogenic variations in medically actionable 59 genes. In this study we evaluated CES data of 622 cases which were tested for various indications. According to ACMG recommendations 59 genes were screened for reportable variations. The detected variations were reviewed using distinct databases and ACMG variation classification guidelines. Among 622 cases 13 (2.1%) had reportable variations including oncogenetic, cardiogenetic disorders, and malignant hyperthermia susceptibility-related genes. In 15 cases (2.4%) heterozygous pathogenic and likely pathogenic variations were detected in genes showing autosomal recessive inheritance. Ten novel variations causing truncated protein or splicing defect were reported. We detected 11 variations having conflicting interpretations in databases and 30 novel variations, predicted as likely pathogenic via insilico analysis tools which further evaluations are needed. As to our knowledge this is the first study investigating secondary findings in Turkish population. To extract the information that may lead to prevent severe morbidities and mortalities from big data is a valuable and lifesaving effort. Results of this study will contrbute to existing knowledge about secondary findings in exome sequencing and will be a pioneer for studies in Turkish population.
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Sequenciamento do Exoma , Testes Genéticos , Genômica , Doenças Raras/diagnóstico , Bases de Dados Genéticas , Exoma/genética , Feminino , Predisposição Genética para Doença , Variação Genética/genética , Humanos , Masculino , Mutação/genética , Doenças Raras/epidemiologia , Doenças Raras/genética , Turquia/epidemiologiaRESUMO
Dubowitz syndrome (DubS) is considered a recognizable syndrome characterized by a distinctive facial appearance and deficits in growth and development. There have been over 200 individuals reported with Dubowitz or a "Dubowitz-like" condition, although no single gene has been implicated as responsible for its cause. We have performed exome (ES) or genome sequencing (GS) for 31 individuals clinically diagnosed with DubS. After genome-wide sequencing, rare variant filtering and computational and Mendelian genomic analyses, a presumptive molecular diagnosis was made in 13/27 (48%) families. The molecular diagnoses included biallelic variants in SKIV2L, SLC35C1, BRCA1, NSUN2; de novo variants in ARID1B, ARID1A, CREBBP, POGZ, TAF1, HDAC8, and copy-number variation at1p36.11(ARID1A), 8q22.2(VPS13B), Xp22, and Xq13(HDAC8). Variants of unknown significance in known disease genes, and also in genes of uncertain significance, were observed in 7/27 (26%) additional families. Only one gene, HDAC8, could explain the phenotype in more than one family (N = 2). All but two of the genomic diagnoses were for genes discovered, or for conditions recognized, since the introduction of next-generation sequencing. Overall, the DubS-like clinical phenotype is associated with extensive locus heterogeneity and the molecular diagnoses made are for emerging clinical conditions sharing characteristic features that overlap the DubS phenotype.
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Eczema/diagnóstico , Eczema/genética , Predisposição Genética para Doença , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/genética , Histona Desacetilases/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Microcefalia/diagnóstico , Microcefalia/genética , Proteínas Repressoras/genética , Adolescente , Criança , Pré-Escolar , Variações do Número de Cópias de DNA/genética , Eczema/patologia , Exoma/genética , Fácies , Feminino , Genoma Humano/genética , Genômica/métodos , Transtornos do Crescimento/patologia , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Microcefalia/patologia , Fenótipo , Sequenciamento do ExomaRESUMO
BACKGROUND: PHARC syndrome (MIM:612674) is a rare neurodegenerative disorder characterized by demyelinating polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataracts (PHARC). The syndrome is caused by mutations in the ABHD12 gene, which encodes αß-hydrolase domain-containing protein 12 related to endocannabinoid metabolism. PHARC syndrome is one of the rare diseases; so far, only 51 patients have been reported in the literature. METHODS: We evaluated the 25-year-old male patient referred to us due to vision loss, cataracts, and hearing loss. Ophthalmological examinations and genetic analyses were performed using targeted next-generation sequencing. RESULTS: In the genetic analysis, the patient was diagnosed with PHARC syndrome by detecting homozygous (NM_001042472.3): c.871del (p.Tyr291IlefsTer28) novel pathogenic variation in the ABHD12 gene. Following the molecular diagnosis, he was referred to the neurology department for reverse phenotyping and sensorimotor demyelinating polyneuropathy was detected in the neurological evaluation. CONCLUSIONS: In this study, we report a novel variation in ABHD12 gene in the first Turkish-origin PHARC patient. We present this study to contribute genotype-phenotype correlation of PHARC syndrome and emphasize the importance of molecular genetic diagnosis in order to determine the appropriate clinical approach. This report is essential for expanding the phenotypic spectrum in different populations and understanding the genotype-phenotype correlation of PHARC syndrome via novel pathogenic variation in the ABHD12 gene.
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Ataxia , Catarata , Perda Auditiva , Polineuropatias , Retinose Pigmentar , Masculino , Humanos , Adulto , Fenótipo , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/genética , Retinose Pigmentar/patologia , Mutação , Síndrome , Catarata/diagnóstico , Catarata/genética , Polineuropatias/diagnóstico , Polineuropatias/genética , Polineuropatias/patologia , Linhagem , Monoacilglicerol Lipases/genéticaRESUMO
Background: The human INHA gene encodes the inhibin subunit alpha protein, which is common to both inhibin A and B. The functional importance of inhibins in male sex development, sexual function, and reproduction remain largely unknown. Objective: We report for the first time two male siblings with homozygous INHAmutations. Methods: The medical files were examined for clinical, biochemical, and imaging data. Genetic analysis was performed using next-generation and Sanger sequencing methods. Results: Two brothers complained of gynecomastia, testicular pain, and had a history of hypospadias. Biochemistry revealed low serum testosterone, high gonadotropin and anti-Mullerian hormone, and very low/undetectable inhibin concentrations, where available. Both patients had azoospermia in the spermiogram. We have identified a homozygous 2 bp deletion (c.208_209delAG, R70Gfs*3) variant, which leads to a truncated INHA protein in both patients, and confirmed heterozygosity in the parents. The external genital development, pubertal onset and progression, reproductive functions, serum gonadotropins, and sex hormones of mother and father, who were heterozygous carriers of the identified mutation, were normal. Conclusion: Homozygosity for INHA mutations causes decreased prenatal and postnatal testosterone production and infertility in males, while the heterozygous female and male carriers of INHA mutations do not have any abnormality in sex development and reproduction.
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Hipogonadismo , Hipospadia , Inibinas/genética , Feminino , Humanos , Hipogonadismo/metabolismo , Hipospadia/genética , Hipospadia/metabolismo , Masculino , Mutação/genética , Irmãos , Testículo/metabolismoRESUMO
LMNA gene encodes A-type lamins and the encoded proteins join the structure of the nuclear lamina and affect the processes of nuclear homeostasis, DNA replication, repair, transcription, and apoptosis. LMNA variants cause a heterogeneous group of diseases known as laminopathies. Phenotypes associated with LMNA variants mainly affect the heart, skeleton, skin, bones, and nervous system. The affected tissues may vary depending on the site of the variant on the gene and the variation type. Complex phenotypes may also occur in some cases, in which findings of premature aging, cardiomyopathy, mandibuloacral dysplasia, lipodystrophy, renal involvement, metabolic involvement, and myopathy coexist. The pleiotropic effect of LMNA variants can result in heterogeneous phenotypes. In this study, we aimed to describe atypical phenotypic characteristics in a patient with familial partial lipodystrophy type 2 associated with LMNA variant, another with mandibuloacral dysplasia, and a third patient with a complex phenotype as well as discuss them in the context of their relationship with the genotype.
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Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Lamina Tipo A/genética , Laminopatias/diagnóstico , Laminopatias/genética , Fenótipo , Alelos , Variação Biológica da População , Genótipo , Humanos , Lipodistrofia Generalizada Congênita/diagnóstico , Lipodistrofia Generalizada Congênita/genética , Especificidade de ÓrgãosRESUMO
Background: Meckel-Gruber syndrome (MKS; OMIM No. 249000) is a rare, in utero lethal disease characterized by occipital encephalocele, polycystic kidneys, and polydactyly. Methodology and Results: In this study, two fetuses diagnosed as having MKS in the prenatal period were evaluated on the basis of ultrasonographic findings, postmortem autopsy findings, and molecular genetic analyses. Using exome sequencing analyses a novel homozygous frameshift variant (NM_015631: c.530delA, p.Lys177Argfs*47) was detected at exon 4 of TCTN3 gene in case 1, and a novel homozygous synonymous variant (NM_025114: c.180G>A, p Lys60Lys) was detected at exon 3 of CEP290 gene in case 2. Case 1 is the first reported case in the literature, which showed the typical MKS clinical feature with a novel frameshift variation in the TCTN3 gene. The variant in case 2 is the first reported synonymous variant of CEP290 gene in the literature, which has been shown to affect splicing in a functional study at the RNA level. Conclusion: TCTN3 gene variants that were rarely associated with the typical MKS phenotype and all cases with these variations have been discussed in the context of genotype-phenotype. The detection of the first synonymous variant of CEP290 gene and the demonstration of its effect on splicing by a functional study are likely to contribute to the molecular etiology of MKS.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Antígenos de Neoplasias/genética , Proteínas Reguladoras de Apoptose/genética , Proteínas de Ciclo Celular/genética , Transtornos da Motilidade Ciliar/genética , Proteínas do Citoesqueleto/genética , Encefalocele/genética , Feto/anormalidades , Doenças Renais Policísticas/genética , Retinose Pigmentar/genética , Adulto , Transtornos da Motilidade Ciliar/diagnóstico , Análise Mutacional de DNA , Encefalocele/diagnóstico , Feminino , Testes Genéticos , Humanos , Cariotipagem , Doenças Renais Policísticas/diagnóstico , Gravidez , Retinose Pigmentar/diagnóstico , Ultrassonografia Pré-Natal , Adulto JovemRESUMO
Polycystic kidney disease (PKD) is a life-threatening condition resulting in end-stage renal disease. Two major forms of PKD are defined according to the inheritance pattern. Autosomal dominant PKD (ADPKD) is characterized by renal cysts, where nearly half of the patients suffers from renal failure in the 7th decade of life. Autosomal recessive PKD (ARPKD) is a rarer and more severe form presenting in childhood. Whole-exome sequencing (WES) analyses was performed to investigate molecular causes of the disease in the fetus. In this study, we present 2 fetuses prenatally diagnosed with PKD in a consanguineous family. WES analysis of the second fetus revealed a homozygous variant (c.740+1G>A) in DNAJB11 which is related to ADPKD. This study reveals that DNAJB11 biallelic mutations may cause an antenatal severe form of ARPKD and contributes to understanding the DNAJB11-related ADPKD phenotype. The possibility of ARPKD due to biallelic mutations in ADPKD genes should be considered in genetic counseling.
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CONTEXT: Developmental disorders of the pituitary gland leading to congenital hypopituitarism can either be isolated or associated with extrapituitary abnormalities (syndromic hypopituitarism). A large number of syndromic hypopituitarism cases are linked to mutations in transcription factors. The forkhead box A2 (FOXA2) is a transcription factor that plays a key role in the central nervous system, foregut, and pancreatic development. OBJECTIVE: This work aims to characterize 2 patients with syndromic hypopituitarism due to FOXA2 gene defects. RESULTS: We report a novel heterozygous nonsense c.616Câ >â T(p.Q206X) variant that leads to a truncated protein that lacks part of the DNA-binding domain of FOXA2, resulting in impaired transcriptional activation of the glucose transporter type 2 (GLUT2)-luciferase reporter. The patient is the sixth patient described in the literature with a FOXA2 mutation, and the first patient exhibiting pancreatic hypoplasia. We also report a second patient with a novel de novo 8.53 Mb deletion of 20p11.2 that encompasses FOXA2, who developed diabetes mellitus that responded to sulfonylurea treatment. CONCLUSION: Our 2 cases broaden the molecular and clinical spectrum of FOXA2-related disease, reporting the first nonsense mutation and the first case of pancreatic dysgenesis.
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Diabetes Mellitus/congênito , Fator 3-beta Nuclear de Hepatócito/genética , Hipopituitarismo/congênito , Pâncreas/anormalidades , Hipófise/anormalidades , Códon sem Sentido , Transportador de Glucose Tipo 2/genética , Humanos , Lactente , Masculino , Síndrome , Fatores de Transcrição/genética , Ativação TranscricionalRESUMO
The apical Par complex, which contains atypical protein kinase C (aPKC), Bazooka (Par-3), and Par-6, is required for establishing polarity during asymmetric division of neuroblasts in Drosophila, and its activity depends on L(2)gl. We show that loss of Ankle2, a protein associated with microcephaly in humans and known to interact with Zika protein NS4A, reduces brain volume in flies and impacts the function of the Par complex. Reducing Ankle2 levels disrupts endoplasmic reticulum (ER) and nuclear envelope morphology, releasing the kinase Ballchen-VRK1 into the cytosol. These defects are associated with reduced phosphorylation of aPKC, disruption of Par-complex localization, and spindle alignment defects. Importantly, removal of one copy of ballchen or l(2)gl suppresses Ankle2 mutant phenotypes and restores viability and brain size. Human mutational studies implicate the above-mentioned genes in microcephaly and motor neuron disease. We suggest that NS4A, ANKLE2, VRK1, and LLGL1 define a pathway impinging on asymmetric determinants of neural stem cell division.