Autosomal dominant spondylocarpotarsal synostosis syndrome: phenotypic homogeneity and genetic heterogeneity.

Spondylocarpotarsal synostosis syndrome (SCT) (OMIM 272460), originally thought to be a failure of normal spine segmentation, is characterized by progressive fusion of vertebras and associates unsegmented bars, scoliosis, short stature, carpal and tarsal synostosis. Cleft palate, sensorineural or mixed hearing loss, joint limitation, clinodactyly, and dental enamel hypoplasia are variable manifestations. Twenty-five patients have been reported. Thirteen affected individuals were siblings from six families and four of these families were consanguineous. In four of those families, Krakow et al. [Krakow et al. (2004) Nat Genet 36:405-410] found homozygosity or compound heterozygosity for mutations in the gene encoding FLNB. This confirmed autosomal recessive inheritance of the disorder. We report on two new patients (a mother and her son) representing the first case of autosomal dominant inheritance. These patients met the clinical and radiological criteria for SCT and did not present any features which could exclude this diagnosis. Molecular analysis failed to identify mutations in NOG and FLNB. SCT is therefore, genetically heterogeneous. Both dominant and autosomal recessive forms of inheritance should be considered during genetic counseling.

Mutation in the human homeobox gene NKX5-3 causes an oculo-auricular syndrome.

Several dysmorphic syndromes affect the development of both the eye and the ear, but only a few are restricted to the eye and the external ear. We describe a developmental defect affecting the eye and the external ear in three members of a consanguineous family. This syndrome is characterized by ophthalmic anomalies (microcornea, microphthalmia, anterior-segment dysgenesis, cataract, coloboma of various parts of the eye, abnormalities of the retinal pigment epithelium, and rod-cone dystrophy) and a particular cleft ear lobule. Linkage analysis and mutation screening revealed in the first exon of the NKX5-3 gene a homozygous 26 nucleotide deletion, generating a truncating protein that lacked the complete homeodomain. Morpholino knockdown expression of the zebrafish nkx5-3 induced microphthalmia and disorganization of the developing retina, thus confirming that this gene represents an additional member implicated in axial patterning of the retina.

Revealing a subclinical salt-losing phenotype in heterozygous carriers of the novel S562P mutation in the alpha subunit of the epithelial sodium channel.

OBJECTIVE: Pseudohypoaldosteronism type I (PHA1) is a rare inborn disease causing severe salt loss. Mutations in the three coding genes of the epithelial sodium channel (ENaC) are responsible for the systemic autosomal recessive form. So far, no phenotype has been reported in heterozygous carriers. PATIENTS: A consanguineous family from Somalia giving birth to a neonate suffering from PHA1 was studied including clinical and hormonal characteristics of the family, mutational analysis of the SCNN1A, SCNN1B, SCNN1G and CFTR genes and in vitro analysis of the functional consequences of a mutant ENaC channel. RESULTS: CFTR mutations have been excluded. SCNN1A gene analysis revealed a novel homozygous c.1684T > C mutation resulting in a S562P substitution in the alphaENaC protein of the patient. Functional analysis showed a significantly reduced S562P channel function compared to ENaC wild type. Protein synthesis and channel subunit assembly were not altered by the S562P mutation. Co-expression of mutant and wild-type channels revealed a dominant negative effect. In heterozygote carriers, sweat sodium and chloride concentrations were increased without additional hormonal or clinical phenotypes. CONCLUSION: Hence, the novel mutation S562P is causing systemic PHA1 in the homozygous state. A thorough clinical investigation of the heterozygote SCNN1A mutation carriers revealed increased sweat sodium and chloride levels consistent with a dominant effect of the mutant S562P allele. Whether this subclinical phenotype is of any consequence for the otherwise asymptomatic heterozygous carriers has to be elucidated.

Depistage mutationnel des genes de la peripherine/RDS, rhodopsine et ROM-1 dans 69 cas index de retinite pigmentaire et autres dystrophies retiniennes [Mutational screening of peripherin/RDS genes, rhodopsin and ROM-1 in 69 index cases with retinitis pigmentosa and other retinal dystrophies]

PURPOSE: Phenotypic, genetic and molecular characterization of 69 index patients with retinitis pigmentosa (RP) and various inherited retinal diseases. PATIENTS AND METHOD: patients went through complete ocular examination and blood samples were drawn for mutational screening of three candidate genes: rhodopsin (RHO), peripherin/RDS, and ROM-1. RESULTS: the most frequent type of RP among our population was the autosomal dominant (43.6%). Three RHO mutations were found among the RP patients. A RDS mutation was detected in three unrelated families segregating dominant macular dystrophy. DISCUSSION AND CONCLUSIONS: 18% of the autosomal dominant RP patients presented a RHO mutation; RDS R172W mutation was present in 25% of the dominant macular dystrophies.

Progresso genético e estrutura populacional do rebanho Nelore no Estado da Bahia

O objetivo deste trabalho foi avaliar a estrutura populacional e o progresso genético e fenotípico de características de desenvolvimento ponderal, em bovinos da raça Nelore, no Estado da Bahia. Foram utilizadas informações de pedigree de animais nascidos no período de 1955 a 2007, e dados dos pesos ajustados aos 205, 365 e 550 dias de idade, de bovinos nascidos de 1970 a 2006. As estimavas dos coeficientes de herdabilidade foram de moderadas a altas, quanto aos pesos ajustados nas três idades. Os rebanhos apresentaram ganho genético positivo nas três características, porém, de baixa magnitude. A mudança fenotípica no decorrer dos anos foi quase exclusivamente relacionada à melhoria ambiental. O tamanho efetivo da população de Nelore do Estado da Bahia tem sido alto em alguns períodos, o que tem levado a menor incremento de endogamia e maiores ganhos genéticos. O intervalo de geração é alto e sua redução é importante para que se possa alcançar maior ganho genético anual.

Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans.

The functional interaction of BAFF and APRIL with TNF receptor superfamily members BAFFR, TACI and BCMA is crucial for development and maintenance of humoral immunity in mice and humans. Using a candidate gene approach, we identified homozygous and heterozygous mutations in TNFRSF13B, encoding TACI, in 13 individuals with common variable immunodeficiency. Homozygosity with respect to mutations causing the amino acid substitutions S144X and C104R abrogated APRIL binding and resulted in loss of TACI function, as evidenced by impaired proliferative response to IgM-APRIL costimulation and defective class switch recombination induced by IL-10 and APRIL or BAFF. Family members heterozygous with respect to the C104R mutation and individuals with sporadic common variable immunodeficiency who were heterozygous with respect to the amino acid substitutions A181E, S194X and R202H had humoral immunodeficiency. Although signs of autoimmunity and lymphoproliferation are evident, the human phenotype differs from that of the Tnfrsf13b-/- mouse model.

Histórico genético e populacional do rebanho Nelore Puro de Origem no Sertão Nordestino

O objetivo deste trabalho foi avaliar o histórico do rebanho Nelore Puro de Origem no Sertão Nordestino por meio da determinação de sua estrutura populacional e da quantificação do progresso genético, fenotípico e ambiental ocorrido em características de desenvolvimento ponderal. Foram utilizadas informações de pedigree de animais nascidos no período de 1964 a 2006 e dados das massas corporais ajustadas aos 205 e 365 dias de idade de bovinos nascidos de 1978 a 2006. O pequeno número de ancestrais explicou a baixa variabilidade genética e os reduzidos valores dos coeficientes de herdabilidade observados para as características de crescimento. O coeficiente de endogamia média e a percentagem de animais endogâmicos na população aumentaram no decorrer das gerações. Contudo, o coeficiente de endogamia médio dos animais endogâmicos diminuiu, o que é indicativo de que os acasalamentos entre parentes próximos estão sendo evitados. O tamanho efetivo da população oscilou de 100 a 200 animais em quase todo o período estudado. Não se constatou ganho genético no período. Contudo, a raça obteve um considerável ganho fenotípico ocasionado por melhorias ambientais.

Genetic improvement and population structure of the Nelore breed in Northern Brazil

The objective of this work was to evaluate the population structure and the genetic and phenotypic progress of Nelore cattle in Northern Brazil. Pedigree information concerning animals born between 1942 and 2006 were analyzed. Population structure was performed using the Endog program. Out of the 140,628 animals studied, 67.7, 14.52 and 3.18% had complete pedigree record of the first, second and third parental generation, respectively. Inbreeding and average relatedness coefficients were low: 0.2 and 0.13%, respectively. However, these parameters may have been underestimated, since information on pedigree was incomplete. The effective number of founders was 370 and the genetic contribution of 10, 50 and 448 most influent ancestors explained 13.2, 28 and 50% of the genetic variability in the population, respectively. The genetic variability for growth traits and population structure demonstrates high probability of increasing productivity through selective breeding. Moreover, management strategies to reduce the currently observed age at first calving and generation intervals are important for Nelore cattle genetic improvement.

Bayesian genetic parameters for body weight and survival of Nile tilapia farmed in Brazil

The objective of this study was to estimate genetic parameters for survival and weight of Nile tilapia (Oreochromis niloticus), farmed in cages and ponds in Brazil, and to predict genetic gain under different scenarios. Survival was recorded as a binary response (dead or alive), during harvest time in the 2008 grow-out period. Genetic parameters were estimated using a Bayesian mixed linear-threshold animal model via Gibbs sampling. The breeding population consisted of 2,912 individual fish, which were analyzed together with the pedigree of 5,394 fish. The heritabilities estimates, with 95% posterior credible intervals, for tagging weight, harvest weight and survival were 0.17 (0.09-0.27), 0.21 (0.12-0.32) and 0.32 (0.22-0.44), respectively. Credible intervals show a 95% probability that the true genetic correlations were in a favourable direction. The selection for weight has a positive impact on survival. Estimated genetic gain was high when selecting for harvest weight (5.07%), and indirect gain for tagging weight (2.17%) and survival (2.03%) were also considerable.

Estrutura populacional de rebanho fechado da raça Nelore da linhagem Lemgruber

O objetivo deste trabalho foi determinar a estrutura populacional e os efeitos causados pela endogamia, em um rebanho fechado da raça Nelore da linhagem Lemgruber. O arquivo de pedigree avaliado incluiu registros de 39.290 animais, 17.646 machos e 21.644 fêmeas, nascidos entre 1951 e 2007. A estrutura da população foi analisada com uso dos programas Poprep e Endog, tendo-se determinado algum nível de endogamia em 61,82% dos animais. O valor do F médio foi 3,02% para toda a população e 4,89% para os animais endogâmicos; e o F máximo foi de 37,5%. O número de ancestrais que contribuiu para a população referência foi 2.380 animais, dos quais apenas sete explicam 50% da variabilidade genética da população. O número efetivo de fundadores (Nf) e o número efetivo de ancestrais (Na) nessa população foram 25 e 21, respectivamente. O incremento esperado de endogamia, causado pela contribuição desequilibrada dos fundadores, foi de 1,62%. A estrutura populacional do rebanho apresenta envelhecimento dos reprodutores, com consequente aumento no intervalo de gerações, além de um contínuo incremento de endogamia e alta percentagem de indivíduos endogâmicos, fatos que comprometem o ganho genético anual e que devem merecer maior atenção dos selecionadores.

Type I osteogenesis imperfecta and multiple osteochondromas in the same child.

A male infant showed a humeral diaphysis fracture at 5 months of age and a distal tibial physis fracture at 2 years of age. A specialized consultant ruled out child abuse. This child had the characteristic features of type I osteogenesis imperfecta: blue sclerae, osseous fragility, and presumably autosomal dominant inheritance, as his father suffered from similar disorders. Later on, multiple painful osteochondromas were also found and some of these were surgically treated. The child's mother showed several peripheral osteochondromas. We describe the follow-up of this patient up to the age of 18 years. To our knowledge, the fortuitous association of these two inherited conditions has not been reported in medical literature.

Familial frontotemporal dementia with ubiquitin inclusion bodies and without motor neuron disease.

Frontotemporal dementia (FTD) is the second most common degenerative dementia after Alzheimer's disease and its Lewy body variant. Clinical pathology can be subdivided in three main neuropathological subtypes: frontal lobe dementia, Pick's disease and FTD with motor neuron disease (MND), all characterised by distinct histological features. Until recently the presence of ubiquitin-positive intraneuronal inclusions in the dentate gyrus, and the temporal and frontal cortex was usually associated with the MND type. Such inclusions were also observed in a few sporadic cases of FTD without or with parkinsonism (FTDP) in the absence of MND. We present here clinical, neuropathological and immunohistochemical data about a Swiss FTD family with FTDP-like features but without MND. Spongiosis and mild gliosis were observed in the grey matter. No neurofibrillary tangles, Pick bodies, Lewy bodies, senile plaques or prion-positive signals were present. However, ubiquitin-positive intracytoplasmic inclusions were detected in various structures but predominantly in the dentate gyrus. These observations support the existence of a familial form of FTDP with ubiquitin-positive intracytoplasmic inclusions (Swiss FTDP family).

Parâmetros populacionais da raça ovina Santa Inês no Brasil

O objetivo deste trabalho foi avaliar a estrutura populacional de ovinos da raça Santa Inês criados no Brasil. Foram utilizados dados de pedigree de 13.216 animais, pertencentes a 53 rebanhos de oito estados brasileiros, nascidos no período de 1976 a 2010. O programa Endog foi utilizado para análise do pedigree e estimação dos parâmetros populacionais. Do total de animais estudados, 80,86% apresentaram pedigree na primeira ascendência, 73,78% na segunda e 67,75% na terceira. O número máximo de gerações conhecidas foi de 19, e a média de gerações equivalentes foi de 4,67. A média do intervalo de gerações foi de 3,22±1,77 anos. O tamanho efetivo da população apresentou média de 172,5 animais. O número de animais fundadores foi 829, mas o número efetivo de fundadores foi apenas 50. Os 17 principais ancestrais explicaram 50% da variabilidade genética total. O coeficiente médio de relação foi de 3,87% e o de endogamia, de 6,92%. Apesar do satisfatório coeficiente médio de endogamia nas últimas gerações, este coeficiente requer monitoramento por sua proximidade do limite recomendável. O fluxo de genes entre os rebanhos é o principal fator para o aumento do tamanho efetivo e a manutenção da variabilidade genética da raça Santa Inês.

Variability of the nucleolar organizer activity in human lymphocytes via Ag-staining.

Chromosomes with Ag staining that varies from one metaphase to the other can be distinguished from those with an Ag-staining that is the same in all metaphases. The intercellular variation of an Ag-NOR can be attributed to many different factors. Whatever the importance of technical factors, they do not seem to account for the large variations in Ag-staining which were observed for each ac. This suggests the existence of a natural intercellular variability of the NOR's activity. The variation of the Ag-stainability of a given NOR, the diversity of Ag-stainings observed on the ten ac of one individual and the differences that exist between individuals raise the question of the existence of a compensation of activity between nucleolar organizers. The study, for each individual, of the mean sum of staining per metaphase reveals that this value is not absolutely constant from one individual to another; in the carriers of Robertsonian fusions it is smaller than in chromosomally normal individuals. The analysis of the transmission shows that inactive NORs remain inactive and that active NORs present a variation in the activity from one generation to the next.