ABSTRACT Homozygous STAT5B mutations causing growth hormone insensitivity with immune dysfunction were described in 10 patients since 2003, including two Brazilian brothers from the south of Brazil. Our objectives were to evaluate the prevalence of their STAT5B mutation in this region and to analyze the presence of a founder effect. We obtained DNA samples from 1,205 local inhabitants, 48 relatives of the homozygous patients and four individuals of another affected family. Genotyping for STAT5B c.424_427del mutation and for two polymorphic markers around it was done through fragment analysis technique. We also determined Y-chromosome and mtDNA haplotypes and genomic ancestry in heterozygous carriers. We identified seven families with STAT5B c.424_427del mutation, with 33 heterozygous individuals. The minor allelic frequency of this mutation was 0.29% in this population (confidence interval 95% 0.08-0.5%), which is significantly higher than the frequency of other pathogenic STAT5B allele variants observed in public databases (p < 0.001). All heterozygous carriers had the same haplotype present in the homozygous patients, found in only 9.4% of non-carriers (p < 0.001), supporting the existence of a founder effect. The Y-chromosome haplotype, mtDNA and genomic ancestry analysis indicated a European origin of this mutation. Our results provide compelling evidence for a founder effect of STAT5B c.424_427del mutation.

Com o aumento da expectativa de vida, visto hoje em todo o planeta, um maior número de indivíduos alcança uma idade avançada em que a manifestação de doenças neurodegenerativas é mais freqüente. Entre essas, a doença de Alzheimer (DA) é a causa mais freqüente de demência. Os achados mais marcantes na DA, em cérebros de pacientes acometidos pela doença, são as placas senis, os emaranhados neurofibrilares e a extensa perda neuronal. No entanto, existe uma carência generalizada de marcadores biológicos preditivos ou com valor diagnóstico para a DA. Estudos de genética molecular permitiram identificar quatro genes consistentemente associados com o maior risco de desenvolvimento da doença: APP, apoE, PSEN1 e PSEN2. No entanto, inúmeros estudos apontam para papel importante de outros genes, fortalecendo a hipótese de uma doença poligênica e multifatorial. Neste sentido, novas abordagens de estudo têm um futuro promissor, podendo indicar uma vasta população de genes ou alterações moleculares que possam explicar o surgimento da doença, vindo a fornecer as bases para a compreensão da DA e também para o delineamento de novas e mais eficazes abordagens de tratamento ou prevenção da doença.

With the increase of the life expectancy that is seen today in the entire planet, a larger number of individuals reaches an advanced age when the manifestation of neurodegenerative illnesses is more frequent. Among these, the Alzheimer's disease (AD) is the most common cause of dementia. The most substantial findings in the brains of patients suffering from AD are the senile plaques, the neurofibrillary tangles and an extensive neuronal loss. However, a general deficiency of predictive biological markers for AD impairs the correct diagnosis and the better understanding of the disease. Studies of molecular genetics allowed the identification of four genes that are consistently linked to AD: APP, apoE, PSEN1 and PSEN2. However, diverse studies demonstrate that other genes also play important roles in the development of AD, strengthening the notion that it is a polygenic illness. Modern large-scale techniques can now be applied in the study of AD, permitting the study of a vast population of genes or molecular alterations that can explain the origin of the illness, offering the basis for the understanding of the pathogenesis of AD and enabling the delineation of new and more efficient approaches to treat and to prevent the sprouting of the disease.

O seqüenciamento de nosso genoma representa um passo essencial no entendimento da biologia humana e no planejamento racional de pesquisas biomédicas. Contudo, é importante notar que o seqüenciamento de um dado genoma é apenas uma parte de um complexo quebra-cabeças. A informação genética deve ser usada como um "mapa", a partir do qual começamos a compreender a base das doenças e a importância da variação genética através da análise da complexidade e do comportamento das regiões reguladoras, genes e proteínas, funções gênicas e sistemas celulares. Apesar dos enormes esforços para identificar genes de susceptibilidade, os resultados de estudos de genética molecular de esquizofrenia até o momento têm sido modestos. O uso apropriado da genômica poderá ajudar imensamente na elucidação das causas da esquizofrenia, permitindo avaliar o papel de novos genes, das variações genéticas, das formas de splicing alternativo, das variações de expressão gênica e de vias metabólicas de interesse. A convergência de dados bioquímicos, de imagem, de neuroanatomia, farmacológicos, clínicos e genéticos permite prever que estamos muito próximos de uma melhor compreensão das bases biológicas da esquizofrenia. A disponibilidade desses avanços terá um enorme impacto na pesquisa desta doença.

The sequencing of our genome represents an essential step in the comprehension of the human biology and in the rational planning of biomedical research. However, it is important to realize that the sequencing of a genome is only a piece of a complex puzzle. The genetic information must be used as a "map", the starting-point to understand the basis of the diseases and the importance of the genetic variation through the analysis of the complexity and behavior of the regulatory regions, genes and proteins, gene functions and cellular systems. Despite the enormous efforts made towards the identification of susceptibility genes for schizophrenia, the results of molecular genetics studies have been modest. The appropriate use of genomics should add more information to help the elucidation of the causes of the schizophrenia, supporting areas such as gene discovery, determination of genetic variations, alternative splicing, analysis of diferential gene expression and in the study of metabolic pathways of interest. The convergence of data from studies of biochemistry, imaging, neuroanatomy, pharmacology, clinical and genetics allows to foresee that we should be near to a better understanding of the biological basis of schizophrenia. The availability of these advances will have a dramatic impact on the research of this disease.

Seventy-two patients with clinical diagnoses of Prader-Willi (PWS; n = 28 patients) or Angelman syndromes (AS; n = 44 patients) were submitted to chromosome analysis, SNRPN-SNURF exon 1 methylation assay, and microsatellite genotyping. Analysis of the methylation pattern confirmed the PWS diagnosis in 18 out of 28 patients and the AS diagnosis in 20 out of 44 patients. FISH and microsatellite analysis detected a deletion in 30 patients (14 PWS and 16 AS). Eight patients had normal FISH results (4 PWS and 4 AS); microsatellite markers showed that these patients had a uniparental disomy (UPD). Based on this study, we propose a strategy for the routine diagnosis of these syndromes that consists of the following steps: 1) methylation analysis, which does not require parental samples; 2) microsatellite genotyping of patient and parents to differentiate deletions, UPD and imprinting mutations; and 3) FISH for otherwise uninformative cases, and whenever parental samples are not available. Of the 34 patients whose PWS or AS diagnoses were not confirmed by laboratory tests, five presented a small extra marker chromosome, identified in three of them as an inv dup(15). One AS patient carried a balanced t(15;15) translocation associated with paternal UPD. Therefore G-banded chromosome analysis should be performed on all such patients, to detect possible structural rearrangements.

The Angelman syndrome (AS) (developmental delay, mental retardation, speech impairment, ataxia, outbursts of laughter, seizures) can result either from a 15q11-q13 deletion, or from paternal uniparental disomy (UPD), imprinting, or UBE3A mutations. We describe here the phenotypic and behavioral variability detected in eight UPD patients out of a group of 58 AS patients studied. All of them presented developmental delay, mental retardation, ataxia, speech impairment, and frequent drooling. Only one had microcephaly, whereas in two of them the OFC (head circumference) was above the 98th percentile. The weight of all patients was above the 50th percentile, and in three of them the height was above the 90th percentile. Three were able to say a few words and to communicate by gestures. Two patients presented hyperphagia, and three presented skin picking, common features in the Prader-Willi syndrome (PWS). Four patients (4/7) had wide-spaced teeth. Five presented seizures, and two others did not manifest frequent laughter. One patient was very different from the others, as he showed a better understanding and abilities to communicate, to play video games and to draw. We suggest here that there seems to be an extreme phenotypic and behavioral variability within the UPD group, and that both typical patients and those with mental retardation, language impairment, happy disposition, and hyperactivity should be tested for AS.

O segmento cromossômico 15q11-q13 é de grande interesse em Genética Humana uma vez que diversos rearranjos estruturais têm sido descritos nessa região (deleções, duplicações e translocações) resultando em fenótipos diferentes como os das síndromes de Prader-Willi (PWS) e Angelman (AS), que foram as primeiras doenças humanas a serem relacionadas com a expressão diferencial de alelos parentais (imprinting genômico). Contrário às leis de Mendel onde a herança parental da informação genética não influencia a expressão gênica, o imprinting genômico é caracterizado por modificações no DNA que produzem diferentes fenótipos dependendo da origem parental da mutação. A manifestação clínica da PWS aparece quando ocorre a perda de genes com expressão exclusivamente paterna, e a AS resulta da perda do gene com expressão exclusivamente materna. Diferentes mecanismos genéticos podem resultar em PWS ou AS como deleções, dissomia uniparental ou mutações no processo de imprinting. Em pacientes com AS existe uma classe adicional de pacientes com mutação no gene UBE3A. Estudos de pacientes com PWS e AS podem ajudar no entendimento do processo de imprinting e, assim, outras regiões do genoma com características similares podem ser localizadas, e diferentes síndromes podem ter seus mecanismos genéticos elucidados.

Chromosomal 15q11-q13 region is of great interest in Human Genetics because many structural rearrangements have been described for it (deletions, duplications and translocations) leading to phenotypes resulting in conditions such as the Prader-Willi (PWS) and Angelman (AS) syndromes which were the first human diseases found to be related to the differential expression of parental alleles (genomic imprinting). Contrary to Mendelian laws where the parental inheritance of genetic information does not influence gene expression, genomic imprinting is characterized by DNA modifications that produce different phenotypes depending on the parental origin of the mutation. Clinical manifestation of PWS appears when the loss of paternally expressed genes occurs and AS results from the loss of a maternally expressed gene. Different genetic mechanisms can lead to PWS or AS, such as deletions, uniparental disomy or imprinting mutation. In AS patients an additional class occurs with mutations on the UBE3A gene. Studies of PWS and AS patients can help us to understand the imprinting process, so that other genomic regions with similar characteristics can be located, and different syndromes can have their genetic mechanisms elucidated.

Os autores descrevem um caso típico de síndrome de Angelman. A paciente apresenta atraso de desenvolvimento neuropsicomotor, deficiência mental, macrostomia, dentes espaçados, convulsões, ausência de fala, andar com a base alargada e instável, crises de risos. Os estudos citogenéticos e moleculares revelaram deleção do segmento 15q11ql3 de origem materna, confirmando o diagnóstico clínico de síndrome de Angelman.

The authors describe the case of a typical Angelman syndrome patient. The proband presents developmental delay, mental retardation, macrostomia, wide-spaced teeth, seizures, absent speech, jerky gait, and paroxysms of laughter. The cytogenetic and molecular studies showed a maternal deletion of 15q11q13. These results are in agreement with the clinical diagnosis of Angelman syndrome.