RESUMO
Intellectual disability (ID) is characterized by an extraordinary genetic heterogeneity, with >250 genes that have been implicated in monogenic forms of ID. Because this complexity precluded systematic testing for mutations and because clinical features are often non-specific, for some of these genes only few cases or families have been unambiguously documented. It is the case of the X-linked gene encoding monoamine oxidase A (MAOA), for which only one nonsense mutation has been identified in Brunner syndrome, characterized in a single family by mild non-dysmorphic ID and impulsive, violent and aggressive behaviors. We have performed targeted high-throughput sequencing of 220 genes, including MAOA, in patients with undiagnosed ID. We identified a c.797_798delinsTT (p.C266F) missense mutation in MAOA in a boy with autism spectrum disorder, attention deficit and autoaggressive behavior. Two maternal uncles carry the mutation and have severe ID, with a history of maltreatment in early childhood. This novel missense mutation decreases MAOA enzymatic activity, leading to abnormal levels of urinary monoamines. The identification of this new point mutation confirms, for the first time since 1993, the monogenic implication of the MAOA gene in ID of various degrees, autism and behavioral disturbances. The variable expressivity of the mutation observed in male patients of this family may involve gene-environment interactions, and the identification of a perturbation in monoamine metabolism should be taken into account when prescribing psychoactive drugs in such patients.
Assuntos
Transtornos de Deficit da Atenção e do Comportamento Disruptivo/genética , Transtornos Globais do Desenvolvimento Infantil/genética , Predisposição Genética para Doença/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Monoaminoxidase/genética , Mutação de Sentido Incorreto , Sequência de Aminoácidos , Sequência de Bases , Saúde da Família , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Modelos Moleculares , Monoaminoxidase/química , Monoaminoxidase/metabolismo , Linhagem , Estrutura Terciária de ProteínaRESUMO
Sperm acrosome is known to play a role in the fertilization of the majority of animal species studied. As a general rule, the acrosome appeared as soon as the fertilization occurred out of aquaeous phase. The biochemical content of acrosome as well as its release mode could suggest it is a simple lysosome. But this would by pass its important morphogenic role in spermiogenesis. Its development is strongly linked to the development of the microtubules manchette system. Molecular data of animal mutagenesis contribute to the understanding of acrosome biogenesis mechanisms. Globozoospermia is a rare but severe human teratozoospermia, characterized by ejaculates entirely consisting of round-headed spermatozoa that lack an acrosome. It originates from a disturbed acrosome biogenesis. Recently, the genetic study of a familial globozoospermia led to highlight a homozygote mutation of the gene SPATA16, linked to the globozoospermic phenotype. This study contributes to the understanding of the mechanisms implied in human acrosome formation.
Assuntos
Acrossomo/fisiologia , Infertilidade Masculina/genética , Espermatozoides/anormalidades , Acrossomo/química , Acrossomo/ultraestrutura , Animais , Consanguinidade , Proteínas de Homeodomínio/genética , Homozigoto , Humanos , Masculino , Mutação , Linhagem , Espermatozoides/ultraestrutura , Proteínas de Transporte VesicularRESUMO
Globozoospermia is a rare (incidence <0.1% in male infertile patients) form of teratozoospermia, mainly characterized by round-headed spermatozoa that lack an acrosome. It originates from a disturbed spermiogenesis, which is expected to be induced by a genetic factor. Several family cases and recessive mouse models with the same phenotype support this expectation. In this study, we present a consanguineous family with three affected brothers, in whom we have identified a homozygous mutation in the spermatogenesis-specific gene SPATA16. This is the first example of a nonsyndromic male infertility condition in humans caused by an autosomal gene defect, and it could also mean that the identification of other partners like SPATA16 could elucidate acrosome formation.