Analysis of MLL2 gene in the first Brazilian family with Kabuki syndrome

Most patients with Kabuki syndrome (KS) are the only person in their family with the condition. However, familial cases of KS have been described showing evidence that this syndrome can be inherited as a dominant trait with variable expressivity. We report on two related individuals with facial findings characteristic of KS. The proposita had arched eyebrows, long and upward slanting palpebral fissures, cleft lip and palate, retromicrognathia, brachydactyly of hands and feet, stubby fingers, nail hypoplasia, and prominent finger pads. Her mother had eyebrows with dispersed lateral half, long and upward slanting palpebral fissures, retrognathia, abnormal and posteriorly rotated ears, prominent finger pads, brachydactyly of feet, learning difficulties, and psychomotor development delay. DNA sequencing revealed a novel missense mutation in the MLL2 gene in both the proposita and her mother. The mutation (p.R5432Q) was found in the exon 51, within the SET domain of the gene, which confers methyltransferase activity on the protein. Therefore, the epigenetic and transcriptional regulatory properties of this protein may be altered and this suggests that the mutation is the cause of phenotype observed in both the patient and her mother. The clinical signs and the molecular evidence in this family further support the notion that KS is an autosomal dominant condition with variable expressivity. To our knowledge this is the first report of a Brazilian family with recurrence of this syndrome. (C) 2012 Wiley Periodicals, Inc.

Chronic mucocutaneous candidiasis and systemic lupus erythematosus: a new variant of chronic mucocutaneous candidiasis?

Chronic mucocutaneous candidiasis (CMC) is characterized by susceptibility to Candida infection of skin, nails, and mucous membranes. Autoimmune endocrinopathies are common in CMC patients, but there are no reports of the involvement of systemic autoimmune disorders. We present here the first case of this kind of association in a patient with an autosomal dominant variant of CMC. The individual had had this disorder since childhood and systemic lupus erythematosus with secondary antiphospholipid syndrome, as well as renal, articular and hepatic manifestations without thymoma.

Auriculo-Condylar Syndrome. Confronting a Diagnostic Challenge

Auriculo-condylar syndrome (ACS) is characterized by typical ears malformation (so-called "question mark" ears), prominent cheeks, microstomia, and abnormality of the temporomandibular joint and condyle of the mandible. In this report we describe a new simplex case and a previously unreported family with affected individuals in three generations documenting clinical variability. Linkage study for markers located in candidate region for ACS1 (1p21.1-q23.3) was excluded in our familial case, reinforcing the hypothesis of genetic heterogeneity for this condition. A review of the literature focusing diagnostic criteria and features of ACS was performed. (C) 2011 Wiley Periodicals, Inc.

Inheritance of resistance to anthracnose stalk rot (Colletotrichum graminicola) in tropical maize inbred lines

Generation means was used to study the mode of inheritance of resistance to anthracnose stalk rot in tropical maize. Each population was comprised of six generations in two trials under a randomized block design. Inoculations were performed using a suspension of 105 conidia mL(-1) applied into the stalk. Internal lesion length was directly measured by opening the stalk thirty days after inoculation. Results indicated contrasting modes of inheritance. In one population, dominant gene effects predominated. Besides, additive x dominant and additive x additive interactions were also found. Intermediate values of heritability indicated a complex resistance inheritance probably conditioned by several genes of small effects. An additive-dominant genetic model sufficed to explain the variation in the second population, where additive gene effects predominated. Few genes of major effects control disease resistance in this cross. Heterosis widely differed between populations, which can be attributed to the genetic background of the parental resistant lines.

Contrasted crustal sources as defined by whole-rock and Sr-Nd-Pb isotope geochemistry of neoproterozoic early post-collisional granitic magmatism within the Southern Brazilian Shear Belt, Camboriu, Brazil

The early phase of post-collisional granitic magmatism in the Camboriu region, south Brazil, is represented by the porphyritic biotite +/- hornblende Rio Pequeno Granite (RPG; 630-620 Ma) and the younger (similar to 610 Ma), equigranular, biotite +/- muscovite Serra dos Macacos Granite (SMG). The two granite types share some geochemical characteristics, but the more felsic SMG constitutes a distinctive group not related to RPG by simple fractionation processes, as indicated by its lower FeOt, TiO2, K2O/Na2O and higher Zr Al2O3, Na2O, Ba and Sr when compared to RPG of similar SiO2 range. Sr-Nd-Pb isotopes require different sources. The SMG derives from old crustal sources, possibly related to the Paleoproterozoic protoliths of the Camboriu Complex, as indicated by strongly negative epsilon Nd-t (-23 to -24) and unradiogenic Pb (e.g., Pb-206/Pb-204 = 16.0-16.3; Pb-207/Pb-204 = 15.3-15.4) and confirmed by previous LA-MC-ICPMS data showing dominant zircon inheritance of Archean to Paleoproterozoic age. In contrast, the RPG shows less negative epsilon Nd-t (-12 to -15) and a distinctive zircon inheritance pattern with no traces of post-1.6 Ga sources. This is indicative of younger sources whose significance in the regional context is still unclear; some contribution of mantle-derived magmas is indicated by coeval mafic dykes and may account for some of the geochemical and isotopic characteristics of the least differentiated varieties of the RPG. The transcurrent tectonics seems to have played an essential role in the generation of mantle-derived magmas despite their emplacement within a low-strain zone. It may have facilitated their interaction with crustal melts which seem to be to a large extent the products of reworking of Paleoproterozoic orthogneisses from the Camboriu Complex. (C) 2012 Elsevier Ltd. All rights reserved.

Aberrant transcript produced by a splice donor site deletion in the TECTA gene is associated with autosomal dominant deafness in a Brazilian family

We ascertained a Brazilian family with nine individuals affected by autosomal dominant nonsyndromic sensorineural hearing loss. The bilateral hearing loss affected mainly mid-high frequencies, was apparently stable with an early onset. Microsatellites close to the DFNA8/DFNA12 locus, which harbors the TECTA gene, showed significant multipoint lod scores (32) close to marker D11S4107. Sequencing of the exons and exon-intron boundaries of the TECTA gene in one affected subject revealed the deletion c.5383 + 5delGTGA in the 5' end of intron 16, that includes the last two bases of the donor splice site consensus sequence. This mutation segregates with deafness within the family. To date, 33 different TECTA mutations associated with autossomal dominant hearing loss have been described. Among them is the mutation reported herein, first described by Hildebrand et al. (2011) in a UK family. The audioprofiles from the UK and Brazilian families were similar. In order to investigate the transcripts produced by the mutated allele, we performed cDNA analysis of a lymphoblastoid cell line from an affected heterozygote with the c.5383 + 5delGTGA and a noncarrier from the same family. The analysis allowed us to identify an aberrant transcript with skipping of exon 16, without affecting the reading frame. One of the dominant TECTA mutations already described, a synonymous substitution in exon 16 (c.5331 G<A), was also shown to affect splicing resulting in an aberrant transcript lacking exon 16. Despite the difference in the DNA level, both the synonymous substitution in exon 16 (c.5331 G<A) and the mutation described herein affect splicing of exon 16, leading to its skipping. At the protein level they would have the same effect, an in-frame deletion of 37 amino-acids (p.S1758Y/G1759_N1795del) probably leading to an impaired function of the ZP domain. Thus, like the TECTA missense mutations associated with dominant hearing loss, the c5383 + 5delGTGA mutation does not have an inactivating effect on the protein. (C) 2012 Elsevier B.V. All rights reserved.

Lipopolysaccharide administration in the dominant mouse destabilizes social hierarchy

Sickness behavior is a set of behavioral changes that are part of an adaptive strategy to overcome infection. Mice that interact with conspecifics displaying sickness behavior also show relevant behavioral changes. In this work we sought to determine the role of sickness behavior display by a dominant mouse as a promoter of hierarchy instability. We treated the dominant mouse within a dyad with lipopolysaccharide (LPS) (400 mu g/kg, i.p.) for three consecutive days and assessed social dominance behavior. Since elder animals display increased inflammatory responses and the behaviors toward conspecifics are influenced by kinship we also assessed whether kinship and age, might influence sickness related hierarchy instability. Our results show that administration of LPS in the dominant mouse promotes social instability within a dyad, and indicates that this instability could be influenced by kinship and age. (C) 2012 Elsevier B.V. All rights reserved.

Incidental mild hyperglycemia in children: two MODY 2 families identified in Brazilian subjects

Maturity-onset diabetes of the young (MODY) is characterized by an autosomal dominant mode of inheritance, early onset of hyperglycemia, and defects of insulin secretion. MODY subtypes described present genetic, metabolic, and clinical differences. MODY 2 is characterized by mild asymptomatic fasting hyperglycemia, and rarely requires pharmacological treatment. Hence, precise diagnosis of MODY is important for determining management and prognosis. We report two heterozygous GCK mutations identified during the investigation of short stature. Case 1: a prepubertal 14-year-old boy was evaluated for constitutional delay of growth and puberty. During follow-up, he showed abnormal fasting glucose (113 mg/dL), increased level of HbA1c (6.6%), and negative beta-cell antibodies. His father and two siblings also had slightly elevated blood glucose levels. The mother had normal glycemia. A GCK heterozygous missense mutation, p.Arg191Trp, was identified in the proband. Eighteen family members were screened for this mutation, and 11 had the mutation in heterozygous state. Case 2: a 4-year-old boy investigated for short stature revealed no other laboratorial alterations than elevated glycemia (118 mg/dL); beta-cell antibodies were negative. His father, a paternal aunt, and the paternal grandmother also had slightly elevated glycemia, whereas his mother had normal glycemia. A GCK heterozygous missense mutation, p.Glu221Lys, was identified in the index patient and in four family members. All affected patients had mild elevated glycemia. Individuals with normal glycemia did not harbor mutations. GCK mutation screening should be considered in patients with chronic mild early-onset hyperglycemia, family history of impaired glycemia, and negative beta-cell antibodies. Arq Bras Endocrinol Metab. 2012;56(8):519-24

Penetrance rate estimation in autosomal dominant conditions

Accurate estimates of the penetrance rate of autosomal dominant conditions are important, among other issues, for optimizing recurrence risks in genetic counseling. The present work on penetrance rate estimation from pedigree data considers the following situations: 1) estimation of the penetrance rate K (brief review of the method); 2) construction of exact credible intervals for K estimates; 3) specificity and heterogeneity issues; 4) penetrance rate estimates obtained through molecular testing of families; 5) lack of information about the phenotype of the pedigree generator; 6) genealogies containing grouped parent-offspring information; 7) ascertainment issues responsible for the inflation of K estimates.

Somatotroph pituitary adenoma with acromegaly and autosomal dominant polycystic kidney disease: SSTR5 polymorphism and PKD1 mutation

A 39-year-old woman with autosomal dominant polycystic kidney disease (ADPKD) presented with acromegaly and a pituitary macroadenoma. There was a family history of this renal disorder. She had undergone surgery for pituitary adenoma 6 years prior. Physical examination disclosed bitemporal hemianopsia and elevation of both basal growth hormone (GH) 106 ng/mL (normal 0-5) and insulin-like growth factor (IGF-1) 811 ng/mL (normal 48-255) blood levels. A magnetic resonance imaging scan disclosed a 3.0 cm sellar and suprasellar mass with both optic chiasm compression and left cavernous sinus invasion. Pathologic, cytogenetic, molecular and in silico analysis was undertaken. Histologic, immunohistochemical and ultrastructural studies of the lesion disclosed a sparsely granulated somatotroph adenoma. Standard chromosome analysis on the blood sample showed no abnormality. Sequence analysis of the coding regions of PKD1 and PKD2 employing DNA from both peripheral leukocytes and the tumor revealed the most common PKD1 mutation, 5014_5015delAG. Analysis of the entire SSTR5 gene disclosed the variant c.142C > A (p.L48M, rs4988483) in the heterozygous state in both blood and tumor, while no pathogenic mutations were noted in the MEN1, AIP, p27Kip1 and SSTR2 genes. To our knowledge, this is the fourth reported case of a GH-producing pituitary adenoma associated with ADPKD, but the first subjected to extensive morphological, ultrastructural, cytogenetic and molecular studies. The physical proximity of the PKD1 and SSTR5 genes on chromosome 16 suggests a causal relationship between ADPKD and somatotroph adenoma.

GATA3 and a dominant regulatory gene expression profile discriminate operational tolerance in human transplantation

Some organ-transplanted patients achieve a state of "operational tolerance" (01) in which graft function is maintained after the complete withdrawal of immunosuppressive drugs. We used a gene panel of regulatory/inflammatory molecules (FOXP3, GATA3, 100, TGFB1, TGFBR1/TBX21, TNF and IFNG) to investigate the gene expression profile in peripheral blood mononuclear cells of renal-transplanted individuals experiencing OT compared to transplanted individuals not displaying OT and healthy individuals (HI). OT subjects showed a predominant regulatory (REG) profile with higher gene expression of GATA3, FOXP3, TGFB1 and TGFB receptor 1 compared to the other groups. This predominant REG gene expression profile displayed stability over time. The significant GATA3 gene and protein expressions in OT individuals suggest that a Th2 deviation may be a relevant pathway to OT. Moreover, the capacity of the REG/INFLAMMA gene panel to discriminate OT by peripheral blood analysis indicates that this state has systemic repercussions. (C) 2011 Elsevier Inc. All rights reserved.

Mutation Spectrum in the Large GTPase Dynamin 2, and Genotype-Phenotype Correlation in Autosomal Dominant Centronuclear Myopathy

Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice-site mutation. Genotype-phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot-Marie-Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue-specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT. Hum Mutat 33: 949-959, 2012. (C) 2012 Wiley Periodicals, Inc.

Genetic aspects of adolescent idiopathic scoliosis in a family with multiple affected members: a research article

Abstract Background The etiology of idiopathic scoliosis remains unknown and different factors have been suggested as causal. Hereditary factors can also determine the etiology of the disease; however, the pattern of inheritance remains unknown. Autosomal dominant, X-linked and multifactorial patterns of inheritances have been reported. Other studies have suggested possible chromosome regions related to the etiology of idiopathic scoliosis. We report the genetic aspects of and investigate chromosome regions for adolescent idiopathic scoliosis in a Brazilian family. Methods Evaluation of 57 family members, distributed over 4 generations of a Brazilian family, with 9 carriers of adolescent idiopathic scoliosis. The proband presented a scoliotic curve of 75 degrees, as determined by the Cobb method. Genomic DNA from family members was genotyped. Results Locating a chromosome region linked to adolescent idiopathic scoliosis was not possible in the family studied. Conclusion While it was not possible to determine a chromosome region responsible for adolescent idiopathic scoliosis by investigation of genetic linkage using microsatellites markers during analysis of four generations of a Brazilian family with multiple affected members, analysis including other types of genomic variations, like single nucleotide polymorphisms (SNPs) could contribute to the continuity of this study.

Degree of multicollinearity and variables involved in linear dependence in additive-dominant models

The objective of this work was to assess the degree of multicollinearity and to identify the variables involved in linear dependence relations in additive-dominant models. Data of birth weight (n=141,567), yearling weight (n=58,124), and scrotal circumference (n=20,371) of Montana Tropical composite cattle were used. Diagnosis of multicollinearity was based on the variance inflation factor (VIF) and on the evaluation of the condition indexes and eigenvalues from the correlation matrix among explanatory variables. The first model studied (RM) included the fixed effect of dam age class at calving and the covariates associated to the direct and maternal additive and non-additive effects. The second model (R) included all the effects of the RM model except the maternal additive effects. Multicollinearity was detected in both models for all traits considered, with VIF values of 1.03 - 70.20 for RM and 1.03 - 60.70 for R. Collinearity increased with the increase of variables in the model and the decrease in the number of observations, and it was classified as weak, with condition index values between 10.00 and 26.77. In general, the variables associated with additive and non-additive effects were involved in multicollinearity, partially due to the natural connection between these covariables as fractions of the biological types in breed composition.

Inheritance of resistance to powdery mildew in pea and pathogenesis-related aspects

The inheritance of resistance to powdery mildew in the pea cultivar MK-10 and some histological aspects of infection were assessed. For the inheritance study, F1, F2, backcrosses and F3 generations of MK-10 crossed with two susceptible populations were evaluated. Histological evaluations included percentage of germinated conidia, percentage of conidia that formed appresoria, percentage of conidia that established colonies, and number of haustoria per colony. Segregation ratios obtained in the resistance inheritance study were compared by Chi-square (ײ) test and the histological data were analyzed by Tukey's test at 5% probability. It was concluded that resistance of MK-10 to powdery mildew is due to a pair of recessive alleles since it is expressed in the pre-penetration stage and completed by post-penetration localized cellular death, characteristic of the presence of the pair of recessive alleles er1er1.