A rare canonical splice-site variant in VPS13B causes attenuated Cohen syndrome.

BACKGROUND: To describe a patient with a history of obesity, retinal dystrophy, type II diabetes, and mild cognitive impairment; found to harbour biallelic splice-site variants in VPS13B. MATERIALS & METHODS: A complete ophthalmic evaluation was performed at Moorfields Eye Hospital (London, United Kingdom), consisting of measurement of best-corrected visual acuity (BCVA), slit lamp and dilated fundus evaluation, colour, autofluorescence and near-infrared retinal imaging, spectral domain-optical coherence tomography, and electroretinogram (ERG). Whole-genome sequencing was performed as part of the UK's 100,000 Genomes Project. RESULTS: A 26-year-old Pakistani man with normal appearance, stature, and head size presented with decreased BCVA and severely constricted visual fields to our Ophthalmic Genetics clinic. He had a history of obesity, type II diabetes, and mild cognitive impairment. His evaluation showed retina-wide, severe photoreceptor dysfunction in both eyes, with undetectable scotopic and photopic ERG waveforms. Genomic analysis identified a homozygous rare splice donor variant in the VPS13B gene (c.5024+2T>C) that was demonstrated to lead to skipping of the in-frame exon 31 (p.Gln1607_Ser1675delinsHis). CONCLUSIONS: Exon 31 skipping in VPS13B may lead to a hypomorphic change, with partial gene function and an incomplete, mild Cohen syndrome-like phenotype.

Expanding the Phenotypic and Genotypic Spectrum of Bietti Crystalline Dystrophy.

The rare form of retinal dystrophy, Bietti crystalline dystrophy, is associated with variations in CYP4V2, a member of the cytochrome P450 family. This study reports patients affected by typical and atypical Bietti crystalline dystrophy, expanding the spectrum of this disease. This is an observational case series of patients with a clinical and molecular diagnosis of Bietti crystalline dystrophy that underwent multimodal imaging. Four unrelated patients are described with two known variants, c.802-8_810del17insGC and c.518T > G (p.Leu173Trp), and one novel missense variant, c.1169G > T (p.Arg390Leu). The patient with the novel homozygous variant had the most severe phenotype resulting in macular hole formation and retinal detachment in both eyes. To the best of our knowledge, there is no association of these features with Bietti crystalline dystrophy. Patient 1 was the youngest patient and had the mildest phenotype with crystals in the retina without chorioretinal atrophy and visual complaints. Patients 2 and 3 presented with fewer crystals and chorioretinal atrophy. These three patients presented a classic phenotype. The fourth patient presented with an atypical and severe phenotype. This study reveals a new genotype and new phenotype associated with this disorder.

Analysis of an NGS retinopathy panel detects chromosome 1 uniparental isodisomy in a patient with RPE65-related leber congenital amaurosis.

Purpose: This study aims to demonstrate the possibility of detecting segmental uniparental isodisomy (iUPD) using a next-generation sequencing gene panel by reporting a Leber congenital amaurosis (LCA) case caused by a homozygous pathogenic variant in RPE65 (c.1022 T > C:p.Leu341Ser) inherited exclusively from the proband's mother.Methods: Samples from the trio (proband, mother, and father) were sequenced with a next-generation sequencing (NGS) retinopathy gene panel (224 genes) and the VCF file containing all variants was used in order to determine single nucleotide variant (SNV) counts from each sample across all chromosomes.Results: Trio analysis showed that of 81 Chr1 inherited variants 41 were exclusively maternal, including 21 homozygous. The other 40 variants were common to both parents. On remaining autosomal chromosomes (Chr2-22) 645 inherited variants were found, 147 of them were exclusively maternal and 132 exclusively paternal. Based on these NGS data, it was possible to note that the proband's chromosomes 1 are more similar to his mother's chromosome 1 than his father's, suggesting the pathogenic homozygous variant found in this patient was inherited exclusively from the mother due to uniparental maternal isodisomy.Conclusions: This study presents a secondary analysis pipeline to identify responsible variants for a phenotype and the correct inheritance pattern, which is a critical step to the proper and accurate genetic counseling of all family members. In addition, this approach could be used to determine iUPD in different Mendelian disorders if the sequencing panel identifies variants spread throughout the genome.

Clinical and molecular findings in a cohort of 152 Brazilian severe early onset inherited retinal dystrophy patients.

Leber congenital amaurosis (LCA) and early-onset retinal dystrophy (EORD) are severe inherited retinal dystrophy that can cause deep blindness childhood. They represent 5% of all retinal dystrophies in the world population and about 10% in Brazil. Clinical findings and molecular basis of syndromic and nonsyndromic LCA/EORD in a Brazilian sample (152 patients/137 families) were studied. In this population, 15 genes were found to be related to the phenotype, 38 new variants were detected and four new complex alleles were discovered. Among 123 variants found, the most common were CEP290: c.2991+1655A>G, CRB1: p.Cys948Tyr, and RPGRIP1: exon10-18 deletion.

TUBGCP4 - associated microcephaly and chorioretinopathy.

Background Microcephaly and chorioretinopathy (MCCRP) is a rare neuro-ophthalmologic disorder that causes microcephaly and chorioretinopathy. In a recessive inheritance pattern, there are three types: MCCRP1; MCCRP2 and MCCRP3. MCCRP3 results from pathogenic variants in the tubulin-gamma complex-associated protein 4 (TUBGCP4) gene.Materials and Methods This is a case report of a patient with a molecular diagnosis defined by mutations in the TUBGCP4 gene. Segregation analyses were carried out.Results The molecular investigation found two heterozygous variants c.1380 G > A (p.Trp460*) a novel nonsense variant, and c.1746 G > T (p Leu582=) a synonymous variant in TUBGCP4. The clinical phenotype was characterized by microcephaly, microphthalmia, chorioretinopathy, a punched-out retinal appearance, dysmorphic facial features, decreased visual acuity, and learning difficulties. The clinical features were similar to those described previously in children with MCCRP3. The proband also had additional features including centripetal obesity, stretch marks, acanthosis nigricans, scoliosis, and hypercholesterolemia. These other features could be part of a ciliopathy syndrome.Conclusions MCCRP2 caused by pathogenic variants in PLK4 is well established as a ciliopathy disease. The role of TUBGCP4 is not well established in the cilium physiology. MCCRP3 may be part of the ciliopathy spectrum.

Synonymous Variant in the CHM Gene Causes Aberrant Splicing in Choroideremia.

Purpose: Choroideremia is an inherited retinal degeneration caused by 280 different pathogenic variants in the CHM gene. Only one silent/synonymous variant (c.1359C>T; p.(Ser453=)) has been reported and was classified as inconclusive based on in silico analysis. This study elucidates the pathogenicity of this variant also found in a Brazilian patient. Methods: Ophthalmological examinations such as color fundus photography, spectral-domain optical coherence tomography, fundus autofluorescence, and macular integrity assessment microperimetry were performed. The subjects' total RNA was extracted from peripheral blood cells. cDNA was synthesized and the amplification between exon 10 and 14 of the CHM mRNA was performed. The amplification products were sequenced by Sanger sequencing and the results were aligned to the reference sequence. Results: The synonymous variant c.1359C>T p.(Ser453=) in the CHM gene is associated with an error in mRNA processing, leading preferentially to production of an aberrant transcript without exon 11 (p.(Gln451Phefs*3)). This anomalous mRNA production is related to typical choroideremia phenotype. Conclusions: These molecular findings reinforce the need for more detailed investigation of silent variants in patients with well-defined phenotype of retinal dystrophies. Molecular and clinical findings provided evidence that c.1359C>T (p.(Gln451Phefs*3)) in CHM should be considered a disease-causing variant.

Retinitis Pigmentosa Due to Rp1 Biallelic Variants.

In the present study, we screened 529 Brazilian individuals affected by inherited retinal disorders. A total of seven unrelated and nonsyndromic patients with RP1 biallelic variants (OMIM # 180100) were diagnosed in our centre and included in the study. They had classic retinitis pigmentosa with diagnosis at the first decade of life. The visual acuities were severely affected at a young age. The fundus aspects were similar among all patients. An atrophic ring was present around the fovea in several cases. All patients had molecular diagnosis, with six different RP1 variants. This study reports two new pathogenic variants - two frameshift duplications (c.1234dupA p.Met412Asnfs*7 and c.1265dupC p.Ala423Cysfs*2) and reinforces other four known pathogenic variants - two frameshift deletions (c.469delG p.Val157Trpfs*16 and c.3843delT p.Pro1282Leufs*12) and two stop gain mutations (c.1186 C > T p.Arg396* and c.1625C > G p.Ser542*). These findings broaden the spectrum of RP1 variants. This study also reviewed the fundus characteristics that clinically could raise the hypothesis of a retinitis pigmentosa due to RP1 gene. It is worthwhile to try to identify the disease-causing variants in each patient since it can provide prognostic information and be useful in genetic consultation and diagnosis in the future.

Retinal dystrophies and variants in PRPH2 / Distrofias retinianas e variantes em PRPH2

ABSTRACT - This report presents three patients diagnosed with macular dystrophies with variants in PRPH2. Peripherin-2, the protein of this gene, is important in the morphogenesis and stabilization of the photoreceptor outer segment. Peripherin-2 deficiencies cause cellular apoptosis. Moreover, pathogenic variants in PRPH2 are associated with various diseases, such as pattern, butterfly-shaped pattern, central areolar, adult-onset vitelliform macular, and cone-rod dystrophies as well as retinitis pigmentosa, retinitis punctata albescens, Leber congenital amaurosis, fundus flavimaculatus, and Stargardt disease.

RESUMO - Este relato apresenta três pacientes com diagnóstico de distrofias maculares com mutações no PRPH2. Periferina 2, a proteína deste gene, é importante na morfogênese e estabilização do segmento externo dos fotorreceptores. Deficiências de periferina 2 causam apoptose celular. Além disso, variantes patogênicas no PRPH2 estão relacionadas a diferentes doenças, como distrofia padrão, distrofia padrão em asa de borboleta, distrofia central areolar, distrofia viteliforme do adulto, retinose pigmentar, distrofia de cones e bastonetes, retinite punctata albscens, amaurose congênita de Leber, fundus flavimaculatus e doença de Stargardt.

Retinal dystrophies and variants in PRPH2.

This report presents three patients diagnosed with macular dystrophies with variants in PRPH2. Peripherin-2, the protein of this gene, is important in the morphogenesis and stabilization of the photoreceptor outer segment. Peripherin-2 deficiencies cause cellular apoptosis. Moreover, pathogenic variants in PRPH2 are associated with various diseases, such as pattern, butterfly-shaped pattern, central areolar, adult-onset vitelliform macular, and cone-rod dystrophies as well as retinitis pigmentosa, retinitis punctata albescens, Leber congenital amaurosis, fundus flavimaculatus, and Stargardt disease.

A New Mutation in IDS Gene Causing Hunter Syndrome: A Case Report.

RATIONALE: Mucopolysaccharidosis type II (Hunter syndrome) is an X-linked multisystem disorder, caused by deficiency of the lysosomal enzyme iduronate-2-sulfatase (I2S). The clinical manifestations of this disease are severe skeletal deformities, airway obstruction, cardiomyopathy, and neurologic deterioration. PATIENT: The patient was 5 years and 6 months boy, with developmental delay, hearing loss, hepatosplenomegaly, and skeletal dysplasia. He was diagnosed with mucopolysaccharidosis type II based on clinical manifestations, biochemical and genetic analysis. OUTCOMES: The patient carries a new mutation (c.879-1210_1007-218del) in hemizygosis in the IDS gene, which was defined as pathogenic according to the 2015 American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines and as responsible for the mucopolysaccharidosis type II phenotype in the patient.

Relative frequency of inherited retinal dystrophies in Brazil.

Among the Brazilian population, the frequency rates of inherited retinal dystrophies and their causative genes are underreported. To increase the knowledge about these dystrophies in our population, we retrospectively studied the medical records of 1,246 Brazilian patients with hereditary retinopathies during 20 years of specialized outpatient clinic care. Of these patients, 559 had undergone at least one genetic test. In this cohort, the most prevalent dystrophies were non-syndromic retinitis pigmentosa (35%), Stargardt disease (21%), Leber congenital amaurosis (9%), and syndromic inherited retinal dystrophies (12%). Most patients had never undergone genetic testing (55%), and among the individuals with molecular test results, 28.4% had negative or inconclusive results compared to 71.6% with a conclusive molecular diagnosis. ABCA4 was the most frequent disease-causing gene, accounting for 20% of the positive cases. Pathogenic variants also occurred frequently in the CEP290, USH2A, CRB1, RPGR, and CHM genes. The relative frequency rates of different inherited retinal dystrophies in Brazil are similar to those found globally. Although mutations in more than 250 genes lead to hereditary retinopathies, only 66 genes were responsible for 70% of the cases, which indicated that smaller and cheaper gene panels can be just as effective and provide more affordable solutions for implementation by the Brazilian public health system.

Exfoliation syndrome associated with LOXL1 gene polymorphisms in a Black patient from Latin America: a case report / Síndrome de esfoliação associada a polimorfismos do gene LOXL1 em paciente negro da América Latina: relato de caso

ABSTRACT A 89-year-old Black female with a 6-year history of advanced open-angle glaucoma was referred to the Glaucoma Service of the Ophthalmology Department - Federal University of São Paulo (UNIFESP). Best-corrected visual acuity was 20/400 in the right eye and 20/60 in the left eye. Pseudoexfoliation material was observed at the iris border, angle, and the anterior lens surface. Anterior biomicroscopy revealed exfoliation material forming an evident peripheral zone and a central disc separated by a clear intermediate zone on the anterior lens surface OU. Gonioscopy showed an open-angle Sampaolesis's line and whitish material deposits OU. Fundus examination revealed a cup-to-disc ratio of 1.0 OU with peripapillary atrophy. Genetic analysis for single nucleo­tide polymorphisms of the lysyl oxidase-like 1 gene linked to exfoliation syndrome identified two such single nucleotide polymorphisms, rs1048661 and rs216524.

RESUMO Uma mulher negra de 89 anos com um histórico de seis anos de glaucoma avançado de ângulo aberto avançado foi encaminhada ao Serviço de Glaucoma do Departamento de Oftalmologia da Universidade Federal de São Paulo (UNIFESP). A acuidade visual melhor corrigida era 20/400 no olho direito e 20/60 no olho esquerdo. Material pseudo-exfoliativo foi observado na borda iriana, ângulo e superfície anterior do cristalino. A biomicroscopia de segmento anterior demonstrou material exfoliativo formando uma zona periférica evidente e um disco central separado por uma zona intermediária livre na cápsula anterior do cristalino. A gonioscopia mostrou uma linha de Sampaolesi de ângulo aberto e depósitos esbranquiçados. O exame de fundo de olho revelou disco óptico com escavação total em ambos os olhos com atrofia peripapilar. A análise genética para polimorfismos de nucleotídeo único do gene semelhante à lysyl oxidase-like 1 ligado à síndrome de esfoliação identificou dois desses polimorfismos de nucleotídeo único, rs1048661 e rs216524.

Exfoliation syndrome associated with LOXL1 gene polymorphisms in a Black patient from Latin America: a case report.

A 89-year-old Black female with a 6-year history of advanced open-angle glaucoma was referred to the Glaucoma Service of the Ophthalmology Department - Federal University of São Paulo (UNIFESP). Best-corrected visual acuity was 20/400 in the right eye and 20/60 in the left eye. Pseudoexfoliation material was observed at the iris border, angle, and the anterior lens surface. Anterior biomicroscopy revealed exfoliation material forming an evident peripheral zone and a central disc separated by a clear intermediate zone on the anterior lens surface OU. Gonioscopy showed an open-angle Sampaolesis's line and whitish material deposits OU. Fundus examination revealed a cup-to-disc ratio of 1.0 OU with peripapillary atrophy. Genetic analysis for single nucleo-tide polymorphisms of the lysyl oxidase-like 1 gene linked to exfoliation syndrome identified two such single nucleotide polymorphisms, rs1048661 and rs216524.

Variants in the ABCA4 gene in a Brazilian population with Stargardt disease.

Purpose: The aim of this study was to analyze and report pathogenic variants in the ABCA4 gene in Brazilian patients with a clinical diagnosis of Stargardt disease. Methods: This retrospective study evaluated variants in the ABCA4 gene in Brazilian patients with Stargardt disease. The patients' visual acuity and age of symptom onset were obtained from previous medical records. The patients were classified according to the autofluorescence patterns. Results: Fifty patients aged between 10 and 65 years from 44 families were included in the study. Among these cases, the mean age of symptom onset was 14 years (range, 5-40 years). ABCA4 gene sequencing was conclusive in 40 patients (80%), negative in two patients (4%), and inconclusive in eight patients (16%). Four families carried homozygous pathogenic variants. Segregation analysis results were available for 23 families. One novel variant was found: p.Ala2084Pro. The most frequent pathogenic variant in this group was p.Arg602Trp (12/100 alleles). Based on the phenotypic characteristics assessed with fundus autofluorescence imaging, 12 patients were classified as having type I phenotype, 16 as having type II, and 18 patients as having type III. The cases classified as type III phenotype included patients who were homozygous for the p.Asn96Asp and p.Arg2030* variants. One patient with a type I phenotype carried the homozygous intronic variant c.3862+1G>A. Conclusions: Next-generation sequencing was effective for the molecular diagnosis of genetic diseases and specifically allowed a conclusive diagnosis in 80% (40/50) of the patients. As the ABCA4 gene does not show a preferential region for pathogenic variants, the diagnosis of Stargardt disease depends on broader analysis of the gene. The most common pathogenic variants in the ABCA4 gene described in the literature were also found in these Brazilian patients. Although some genotype-phenotype correlations were found, more studies regarding the progression of Stargardt disease will help increase our understanding of the pathogenicity of these gene variants.

Novel Complex ABCA4 Alleles in Brazilian Patients With Stargardt Disease: Genotype-Phenotype Correlation.

Purpose: To analyze the presence of complex alleles of the ABCA4 gene in Brazilian patients with Stargardt disease and to assess the correlation with clinical features. Methods: This was an observational cross-sectional study. Patients with a diagnosis of Stargardt disease who presented three pathogenic variants of the ABCA4 gene or who had variants previously described as complex alleles were included. The relatives of these probands were evaluated in the segregation analysis. The patients were evaluated based on age at symptom onset and visual acuity, and the clinical characteristics were classified according to the findings observed on autofluorescence examination. Results: Among the 47 families analyzed, approximately 30% (14/47) presented complex alleles. The segregation analysis in 14 families with cases of Stargardt disease identified three novel complex alleles and one previously described complex allele. The known complex allele p.[Leu541Pro; Ala1038Val] was identified in two families. The novel complex alleles identified were p.[Leu541Pro; Arg1443His] in five families, p.[Ser1642Arg; Val1682_Val1686del] in seven families, and p.[Pro1761Arg; Arg2106Cys] in one family. Furthermore, four new variants (p.Lys22Asn, p.Asp915Asn, p.Glu1447Val, and p.Pro1761Arg) were identified in the second allele of the ABCA4 gene. Conclusions: Segregation analysis is important in order to confirm the molecular diagnosis of patients with Stargardt disease, given the frequency of complex alleles in the ABCA4 gene. The various pathogenic variation combinations observed in this study were associated with different phenotypes.

The correlation between CRB1 variants and the clinical severity of Brazilian patients with different inherited retinal dystrophy phenotypes.

Inherited retinal dystrophies are characterized by progressive retina degeneration and mutations in at least 250 genes have been associated as disease-causing. CRB1 is one of many genes analyzed in molecular diagnosis for inherited retinal dystrophy. Crumbs homolog-1 protein encoded by CRB1 is important for cell-to-cell contact, polarization of epithelial cells and the morphogenesis of photoreceptors. Pathogenic variants in CRB1 lead to a huge variety of phenotypes ranging from milder forms of inherited retinal dystrophy, such as retinitis pigmentosa to more severe phenotypes such as Leber congenital amaurosis. In this study, seven novel likely-pathogenic variants were identified: four missense variants (p.Leu479Pro, p.Ala921Pro, p.Cys948Arg and p.Asp1031Asn), two frameshift deletions (c.2536_2542del7 and c.3460_3461delTG) and one frameshift indel variant (c.276_294delinsTGAACACTGTAC). Furthermore, two patients with cone-rod dystrophy due to mutations in CRB1 were reported, supporting previous data, in which mutations in CRB1 can also cause cone-rod dystrophy. Finally, our data suggested there was a direct relation between phenotype severity and the mutation effect on protein functionality in 15 Brazilian CRB1 patients.

PROM1 gene variations in Brazilian patients with macular dystrophy.

BACKGROUND: Although the pathogenicity of the prominin-1 (PROM1) gene has already been described as associated with autosomal dominant Stargardt disease, little is known about sequence variations in this gene. PURPOSE: The aim of this study was to evaluate PROM1 gene sequence variations in patients with macular dystrophy. MATERIAL AND METHODS: This retrospective study evaluated variations in the PROM1 gene detected by next-generation sequencing test in patients with macular dystrophy and Stargardt disease. RESULTS: Of 25 medical records of patients with Stargardt disease, three records of patients with PROM1 gene sequence variations were selected for the study. The p.Asp776Val and p.Asp829Asn variants were detected in cases 1 and 2, respectively, and predicted to be pathogenic; they were probably responsible for macular dystrophy in these patients. Case 3 showed a p.Ala643Gly variant in the PROM1 gene and a single variation in the ABCA4 gene, but molecular testing results were inconclusive. CONCLUSIONS: In cases of Stargardt disease, where molecular testing results are inconclusive for pathogenic variations in the ABCA4 gene, variations in the PROM1 gene may occur and be considered responsible for the disease in the molecular analysis. This study described three cases in which variations in PROM1 gene may play a role in the pathogenesis of macular dystrophy or be associated with both autosomal recessive and autosomal dominant inheritance.

Novel GAA mutations in patients with Pompe disease.

Pompe disease is an autosomal recessive disorder linked to GAA gene that leads to a multi-system intralysosomal accumulation of glycogen. Mutation identification in the GAA gene can be very important for early diagnosis, correlation between genotype-phenotype and therapeutic intervention. For this purpose, peripheral blood from 57 individuals susceptible to Pompe disease was collected and all exons of GAA gene were amplified; the sequences and the mutations were analyzed in silico to predict possible impact on the structure and function of the human protein. In this study, 46 individuals presented 33 alterations in the GAA gene sequence, among which five (c.547-67C>G, c.547-39T>G, p.R437H, p.L641V and p.L705P) have not been previously described in the literature. The alterations in the coding region included 15 missense mutations, three nonsense mutations and one deletion. One insertion and other 13 single base changes were found in the non-coding region. The mutation p.G611D was found in homozygosis in a one-year-old child, who presented low levels of GAA activity, hypotonia and hypertrophic cardiomyopathy. Two patients presented the new mutation p.L705P in association with c.-32-13T>G. They had low levels of GAA activity and developed late onset Pompe disease. In our study, we observed alterations in the GAA gene originating from Asians, African-Americans and Caucasians, highlighting the high heterogeneity of the Brazilian population. Considering that Pompe disease studies are not very common in Brazil, this study will help to better understand the potential pathogenic role of each change in the GAA gene. Furthermore, a precise and early molecular analysis improves genetic counseling besides allowing for a more efficient treatment in potential candidates.

Kinin B1 receptor in adipocytes regulates glucose tolerance and predisposition to obesity.

BACKGROUND: Kinins participate in the pathophysiology of obesity and type 2 diabetes by mechanisms which are not fully understood. Kinin B(1) receptor knockout mice (B(1) (-/-)) are leaner and exhibit improved insulin sensitivity. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that kinin B(1) receptors in adipocytes play a role in controlling whole body insulin action and glucose homeostasis. Adipocytes isolated from mouse white adipose tissue (WAT) constitutively express kinin B(1) receptors. In these cells, treatment with the B(1) receptor agonist des-Arg(9)-bradykinin improved insulin signaling, GLUT4 translocation, and glucose uptake. Adipocytes from B(1) (-/-) mice showed reduced GLUT4 expression and impaired glucose uptake at both basal and insulin-stimulated states. To investigate the consequences of these phenomena to whole body metabolism, we generated mice where the expression of the kinin B(1) receptor was limited to cells of the adipose tissue (aP2-B(1)/B(1) (-/-)). Similarly to B(1) (-/-) mice, aP2-B(1)/B(1) (-/-) mice were leaner than wild type controls. However, exclusive expression of the kinin B(1) receptor in adipose tissue completely rescued the improved systemic insulin sensitivity phenotype of B(1) (-/-) mice. Adipose tissue gene expression analysis also revealed that genes involved in insulin signaling were significantly affected by the presence of the kinin B(1) receptor in adipose tissue. In agreement, GLUT4 expression and glucose uptake were increased in fat tissue of aP2-B(1)/B(1) (-/-) when compared to B(1) (-/-) mice. When subjected to high fat diet, aP2-B(1)/B(1) (-/-) mice gained more weight than B(1) (-/-) littermates, becoming as obese as the wild types. CONCLUSIONS/SIGNIFICANCE: Thus, kinin B(1) receptor participates in the modulation of insulin action in adipocytes, contributing to systemic insulin sensitivity and predisposition to obesity.

New mutations in the GLA gene in Brazilian families with Fabry disease.

Fabry disease (FD) is an X-linked inborn error of glycosphingolipid catabolism that results from mutations in the alpha-galactosidase A (GLA) gene. Evaluating the enzymatic activity in male individuals usually performs the diagnosis of the disease, but in female carriers the diagnosis based only on enzyme assays is often inconclusive. In this work, we analyzed 568 individuals from 102 families with suspect of FD. Overall, 51 families presented 38 alterations in the GLA gene, among which 19 were not previously reported in literature. The alterations included 17 missense mutations, 7 nonsense mutations, 7 deletions, 6 insertions and 1 in the splice site. Six alterations (R112C, R118C, R220X, R227X, R342Q and R356W) occurred at CpG dinucleotides. Five mutations not previously described in the literature (A156D, K237X, A292V, I317S, c.1177_1178insG) were correlated with low GLA enzyme activity and with prediction of molecular damages. From the 13 deletions and insertions, 7 occurred in exons 6 or 7 (54%) and 11 led to the formation of a stop codon. The present study highlights the detection of new genomic alterations in the GLA gene in the Brazilian population, facilitating the selection of patients for recombinant enzyme-replacement trials and offering the possibility to perform prenatal diagnosis.