RESUMO
Gorham-Stout disease (GSD), also called vanishing bone disease, is a rare osteolytic disease, frequently associated with lymphangiomatous tissue proliferation. The causative genetic background has not been noted except for a case with a somatic mutation in KRAS. However, in the present study, we encountered a case of GSD from a consanguineous family member. Whole-exome sequencing (WES) analysis focusing on rare recessive variants with zero homozygotes in population databases identified a homozygous missense variant (c.823G > C, p.Asp275His) in gasdermin D (GSDMD) in the patient and heterozygous in his unaffected brother. Because this variant affects the Asp275 residue that is involved in proteolytic cleavage by caspase-11 (as well as -4 and -5) to generate an activating p30 fragment required for pyroptotic cell death and proinflammation, we confirmed the absence of this cleavage product in peripheral monocytic fractions from the patient. A recent study indicated that a shorter p20 fragment, generated by further cleavage at Asp88, has a cell-autonomous function to suppress the maturation of osteoclasts to resorb bone matrix. Thus, the present study suggests for the first time the existence of hereditary GSD cases or novel GSD-like diseases caused by GSDMD deficiency. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
RESUMO
Mutations in proteins involved in cell division and chromosome segregation, such as microtubule-regulating, centrosomal and kinetochore proteins, are associated with microcephaly and/or short stature. In particular, the kinetochore plays an essential role in mitosis and cell division by mediating connections between chromosomal DNA and spindle microtubules. To date, only a few genes encoding proteins of the kinetochore complex have been identified as causes of syndromes that include microcephaly. We report a male patient with a rare de novo missense variant in NUF2, after trio whole-exome sequencing analysis. The patient presented with microcephaly and short stature, with additional features, such as bilateral vocal cord paralysis, micrognathia and atrial septal defect. NUF2 encodes a subunit of the NDC80 complex in the outer kinetochore, important for correct microtubule binding and spindle assembly checkpoint. The mutated residue is buried at the calponin homology (CH) domain at the N-terminus of NUF2, which interacts with the N-terminus of NDC80. The variant caused the loss of hydrophobic interactions in the core of the CH domain of NUF2, thereby impairing the stability of NDC80-NUF2. Analysis using a patient-derived lymphoblastoid cell line revealed markedly reduced protein levels of both NUF2 and NDC80, aneuploidy, increased micronuclei formation and spindle abnormality. Our findings suggest that NUF2 may be the first member of the NDC80 complex to be associated with a human disorder.
Assuntos
Anormalidades Múltiplas/genética , Aneuploidia , Proteínas de Ciclo Celular/genética , Transtornos Cromossômicos/genética , Segregação de Cromossomos , Mutação de Sentido Incorreto , Anormalidades Múltiplas/patologia , Adolescente , Estatura/genética , Linhagem Celular , Transtornos Cromossômicos/patologia , Proteínas do Citoesqueleto/genética , Regulação para Baixo , Transtornos do Crescimento/genética , Humanos , Masculino , Microcefalia/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Fuso Acromático/patologia , Ubiquitina/metabolismo , Sequenciamento Completo do GenomaRESUMO
Early-onset developmental and epileptic encephalopathy (DEE) is a group of devastating disorders that appear during the neonatal and infantile periods. Despite great progress in the discovery of genes leading to early-onset DEE, many cases with unexplained etiology remain. Furthermore, to date, the association of copy number variations (CNVs) with early-onset DEE has seldom been addressed. Here, we investigated the contribution of CNVs to epilepsy in a cohort of Japanese children with a variety of early-onset DEEs. Single nucleotide polymorphism (SNP) array analysis was performed for 83 cases that were previously negative for pathogenic single nucleotide variants (SNVs) in 109 genes known or suspected to cause epileptic seizures. Rare CNVs were detected in a total of 12 cases (14.4%), of which three cases (3.6%) involved clearly pathogenic CNVs and nine cases (10.8%) were CNVs of uncertain significance. The three pathogenic CNVs included two de novo heterozygous deletions involving known epileptic encephalopathy genes, such as GABRG2 and PCDH19, and one maternally inherited duplication encompassing MECP2. Our findings indicate rare CNVs are also relevant for the diagnosis of early-onset DEEs, highlighting the importance of not relying only on the investigation of SNVs/small indels at the risk of missing large deletions and duplications.
Assuntos
Variações do Número de Cópias de DNA/genética , Deficiências do Desenvolvimento/genética , Convulsões/genética , Espasmos Infantis/genética , Caderinas/genética , Criança , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Proteína 2 de Ligação a Metil-CpG/genética , Polimorfismo de Nucleotídeo Único/genética , Protocaderinas , Receptores de GABA-A/genética , Convulsões/fisiopatologia , Espasmos Infantis/fisiopatologiaRESUMO
The CASK gene (Xp11.4) is highly expressed in the mammalian nervous system and plays several roles in neural development and synaptic function. Loss-of-function mutations of CASK are associated with intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH), especially in females. Here, we present a comprehensive investigation of 41 MICPCH patients, analyzed by mutational search of CASK and screening of candidate genes using an SNP array, targeted resequencing and whole-exome sequencing (WES). In total, we identified causative or candidate genomic aberrations in 37 of the 41 cases (90.2%). CASK aberrations including a rare mosaic mutation in a male patient, were found in 32 cases, and a mutation in ITPR1, another known gene in which mutations are causative for MICPCH, was found in one case. We also found aberrations involving genes other than CASK, such as HDAC2, MARCKS, and possibly HS3ST5, which may be associated with MICPCH. Moreover, the targeted resequencing screening detected heterozygous variants in RELN in two cases, of uncertain pathogenicity, and WES analysis suggested that concurrent mutations of both DYNC1H1 and DCTN1 in one case could lead to MICPCH. Our results not only identified the etiology of MICPCH in nearly all the investigated patients but also suggest that MICPCH is a genetically heterogeneous condition, in which CASK inactivating mutations appear to account for the majority of cases.
Assuntos
Cerebelo/anormalidades , Deficiência Intelectual/etiologia , Deficiência Intelectual/genética , Microcefalia/etiologia , Microcefalia/genética , Mutação/genética , Malformações do Sistema Nervoso/etiologia , Malformações do Sistema Nervoso/genética , Adolescente , Animais , Criança , Pré-Escolar , Dineínas do Citoplasma/genética , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/genética , Complexo Dinactina/genética , Feminino , Predisposição Genética para Doença/genética , Guanilato Quinases/genética , Histona Desacetilase 2/genética , Humanos , Lactente , Receptores de Inositol 1,4,5-Trifosfato/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Proteínas de Membrana/genética , Substrato Quinase C Rico em Alanina Miristoilada , Mutação Puntual/genética , Proteína Reelina , SuínosRESUMO
Intellectual disability (ID) is a heterogeneous condition affecting 2-3% of the population, often associated with multiple congenital anomalies (MCA). The genetic cause remains largely unexplained for most cases. To investigate the causes of ID/MCA of unknown etiology in the Japanese population, 645 subjects have been recruited for the screening of pathogenic copy-number variants (CNVs). Two screenings using bacterial artificial chromosome (BAC) arrays were previously performed, which identified pathogenic CNVs in 133 cases (20.6%; Hayashi et al., J. Hum. Genet., 2011). Here, we present the findings of the third screening using a single-nucleotide polymorphism (SNP) array, performed in 450 negative cases from our previous report. Pathogenic CNVs were found in 22 subjects (4.9%), in which 19 CNVs were located in regions where clinical significance had been previously established. Among the 22 cases, we identified PPFIA2 as a novel candidate gene for ID. Analysis of copy-neutral loss of heterozygosity (CNLOH) detected one case in which the CNLOH regions seem to be significant. The SNP array detected a modest fraction of small causative CNVs, which is explained by the fact that the majority of causative CNVs have larger sizes, and those had been mostly identified in the two previous screenings.
Assuntos
Anormalidades Múltiplas/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Deficiência Intelectual/genética , Proteínas de Membrana/genética , Anormalidades Múltiplas/fisiopatologia , Aberrações Cromossômicas , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA/genética , Feminino , Genoma Humano , Genômica , Humanos , Deficiência Intelectual/fisiopatologia , Perda de Heterozigosidade/genética , Masculino , Fenótipo , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Samples from 30 deaf probands exhibiting features suggestive of syndromic mitochondrial deafness or from families with maternal transmission of deafness were selected for investigation of mutations in the mitochondrial genes MT-RNR1 and MT-TS1. Patients with mutation m.1555A>G had been previously excluded from this sample. In the MT-RNR1 gene, five probands presented the m.827A>G sequence variant, of uncertain pathogenicity. This change was also detected in 66 subjects of an unaffected control sample of 306 Brazilian individuals from various ethnic backgrounds. Given its high frequency, we consider it unlikely to have a pathogenic role on hereditary deafness. As to the MT-TS1 gene, one proband presented the previously known pathogenic m.7472insC mutation and three probands presented a novel variant, m.7462C>T, which was absent from the same control sample of 306 individuals. Because of its absence in control samples and association with a family history of hearing impairment, we suggest it might be a novel pathogenic mutation.