Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 345
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Am J Hum Genet ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31587868

RESUMO

NKAP is a ubiquitously expressed nucleoplasmic protein that is currently known as a transcriptional regulatory molecule via its interaction with HDAC3 and spliceosomal proteins. Here, we report a disorder of transcriptional regulation due to missense mutations in the X chromosome gene, NKAP. These mutations are clustered in the C-terminal region of NKAP where NKAP interacts with HDAC3 and post-catalytic spliceosomal complex proteins. Consistent with a role for the C-terminal region of NKAP in embryogenesis, nkap mutant zebrafish with a C-terminally truncated NKAP demonstrate severe developmental defects. The clinical features of affected individuals are highly conserved and include developmental delay, hypotonia, joint contractures, behavioral abnormalities, Marfanoid habitus, and scoliosis. In affected cases, transcriptome analysis revealed the presence of a unique transcriptome signature, which is characterized by the downregulation of long genes with higher exon numbers. These observations indicate the critical role of NKAP in transcriptional regulation and demonstrate that perturbations of the C-terminal region lead to developmental defects in both humans and zebrafish.

2.
Biol Pharm Bull ; 42(9): 1596-1599, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474720

RESUMO

Joint hypermobility syndrome (JHS) (also termed hypermobility type Ehlers-Danlos syndrome, hEDS) is a heritable connective tissue disorder that is characterized by generalized joint hypermobility, chronic pain, fatigue, and minor skin changes. Initially, it was reported that there is a small subset of patients with JHS/hEDS who have haploinsufficiency of tenascin-X (TNX). However, the relationship between TNXB and JHS/hEDS has not been reported at all afterwards. EDS was reclassified into thirteen types in 2017, and the causative gene of JHS/hEDS remained to be identified. Therefore, in this study in order to determine whether JHS/hEDS can be diagnosed by the concentrations of serum form of TNX (sTNX), we measured the concentrations of sTNX in 17 JHS/hEDS patients. The sTNX concentrations in half of the JHS/hEDS patients were significantly lower than those in healthy individuals. No mutations, insertions or deletions were detected in the TNX exon sequence of the JHS/hEDS patients except for one in patient. That patient has a heterozygous mutation. A correlation between sTNX concentration and mutation of the TNXB genomic sequence was not found in the JHS/hEDS patients. These results indicate that the decrease in sTNX concentration could be used as a risk factor for JHS/hEDS.

3.
Ann Neurol ; 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31433517

RESUMO

Leukoencephalopathies comprise a broad spectrum of disorders, but the genetic background of adult leukoencephalopathies has rarely been assessed. In this study, we analyzed 101 Japanese patients with genetically unresolved adult leukoencephalopathy using whole-exome sequencing and repeat-primed PCR for detecting GGC expansion in NOTCH2NLC. NOTCH2NLC was recently identified as the cause of neuronal intranuclear inclusion disease. We found 12 patients with GGC expansion in NOTCH2NLC as the most frequent cause of adult leukoencephalopathy followed by NOTCH3 variants in our cohort. Further, we found one case with de novo GGC expansion, which might explain the underlying pathogenesis of sporadic cases. This article is protected by copyright. All rights reserved.

4.
J Hum Genet ; 64(11): 1107-1116, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31409854

RESUMO

The recent advent of long-read sequencing technologies is expected to provide reasonable answers to genetic challenges unresolvable by short-read sequencing, primarily the inability to accurately study structural variations, copy number variations, and homologous repeats in complex parts of the genome. However, long-read sequencing comes along with higher rates of random short deletions and insertions, and single nucleotide errors. The relatively higher sequencing accuracy of short-read sequencing has kept it as the first choice of screening for single nucleotide variants and short deletions and insertions. Albeit, short-read sequencing still suffers from systematic errors that tend to occur at specific positions where a high depth of reads is not always capable to correct for these errors. In this study, we compared the genotyping of mitochondrial DNA variants in three samples using PacBio's Sequel (Pacific Biosciences Inc., Menlo Park, CA, USA) long-read sequencing and illumina's HiSeqX10 (illumine Inc., San Diego, CA, USA) short-read sequencing data. We concluded that, despite the differences in the type and frequency of errors in the long-reads sequencing, its accuracy is still comparable to that of short-reads for genotyping short nuclear variants; due to the randomness of errors in long reads, a lower coverage, around 37 reads, can be sufficient to correct for these random errors.

5.
Genet Med ; 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31263216

RESUMO

PURPOSE: We observed four individuals in two unrelated but consanguineous families from Portugal and Brazil affected by early-onset retinal degeneration, sensorineural hearing loss, microcephaly, intellectual disability, and skeletal dysplasia with scoliosis and short stature. The phenotype precisely matched that of an individual of Azorean descent published in 1986 by Liberfarb and coworkers. METHODS: Patients underwent specialized clinical examinations (including ophthalmological, audiological, orthopedic, radiological, and developmental assessment). Exome and targeted sequencing was performed on selected individuals. Minigene constructs were assessed by quantitative polymerase chain reaction (qPCR) and Sanger sequencing. RESULTS: Affected individuals shared a 3.36-Mb region of autozygosity on chromosome 22q12.2, including a 10-bp deletion (NM_014338.3:c.904-12_904-3delCTATCACCAC), immediately upstream of the last exon of the PISD (phosphatidylserine decarboxylase) gene. Sequencing of PISD from paraffin-embedded tissue from the 1986 case revealed the identical homozygous variant. In HEK293T cells, this variant led to aberrant splicing of PISD transcripts. CONCLUSION: We have identified the genetic etiology of the Liberfarb syndrome, affecting brain, eye, ear, bone, and connective tissue. Our work documents the migration of a rare Portuguese founder variant to two continents and highlights the link between phospholipid metabolism and bone formation, sensory defects, and cerebral development, while raising the possibility of therapeutic phospholipid replacement.

6.
J Hum Genet ; 64(10): 967-978, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31337854

RESUMO

Cornelia de Lange syndrome (CdLS) is a rare multisystem disorder with specific dysmorphic features. Pathogenic genetic variants encoding cohesion complex subunits and interacting proteins (e.g., NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major causes of CdLS. However, there are many clinically diagnosed cases of CdLS without pathogenic variants in these genes. To identify further genetic causes of CdLS, we performed whole-exome sequencing in 57 CdLS families, systematically evaluating both single nucleotides variants (SNVs) and copy number variations (CNVs). We identified pathogenic genetic changes in 36 out of 57 (63.2 %) families, including 32 SNVs and four CNVs. Two known CdLS genes, NIPBL and SMC1A, were mutated in 23 and two cases, respectively. Among the remaining 32 individuals, four genes (ANKRD11, EP300, KMT2A, and SETD5) each harbored a pathogenic variant in a single individual. These variants are known to be involved in CdLS-like. Furthermore, pathogenic CNVs were detected in NIPBL, MED13L, and EHMT1, along with pathogenic SNVs in ZMYND11, MED13L, and PHIP. These three latter genes were involved in diseases other than CdLS and CdLS-like. Systematic clinical evaluation of all patients using a recently proposed clinical scoring system showed that ZMYND11, MED13L, and PHIP abnormality may cause CdLS or CdLS-like.

7.
Am J Hum Genet ; 105(2): 403-412, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31303265

RESUMO

POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder.

8.
J Hum Genet ; 64(9): 885-890, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31270375

RESUMO

Pediatric hypertension can cause hypertensive emergencies, including hemorrhagic stroke, contributing to rare but serious childhood morbidity and mortality. Renovascular hypertension (RVH) is one of the major causes of secondary hypertension in children. Grange syndrome (MIM#602531) is a rare disease characterized by multiple stenosis or occlusion of the renal, abdominal, coronary, and cerebral arteries, which can cause phenotypes of RVH and fibromuscular dysplasia (MIM#135580). We report the case of a 7-year-old girl with Grange syndrome who showed RVH and multiple seizure episodes. At 1 year of age, she experienced seizures and sequential hemiparesis caused by a left thalamic hemorrhage without cerebral vascular anomalies. Chronic hypertension was observed, and abdominal computed tomography angiography showed characteristic bilateral renal artery stenosis. Whole-exome sequencing revealed a novel homozygous pathogenic variant in the YY1AP1 gene (NM_001198903.1: c.1169del: p.Lys390Argfs*12). Biallelic YY1AP1 mutations are known to cause Grange syndrome. Unlike previously reported patients, our patient presented with intracerebral hemorrhagic stroke without anomalous brain artery or bone fragility. The phenotype in our patient may help better understand this ultra-rare syndrome. Grange syndrome should be considered in patients presenting with childhood-onset hypertension and/or hemorrhagic stroke for early clinical intervention.

9.
Nat Commun ; 10(1): 2506, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31175295

RESUMO

Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs (P = 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (P = 2.04 × 10-6) enrichment of damaging de novo mutations in NF1, a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders.


Assuntos
Variação Genética , Espasmos Infantis/genética , Proteínas Adaptadoras de Transporte Vesicular/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , DNA (Citosina-5-)-Metiltransferases/genética , Epilepsias Mioclônicas/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Lactente , Japão , Síndrome de Lennox Gastaut/genética , Modelos Logísticos , Mutação , Neurofibromina 1/genética , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , Canais de Cátion TRPM/genética , Sequenciamento Completo do Exoma
10.
Neurology ; 93(3): e237-e251, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31197031

RESUMO

OBJECTIVE: Intensive genetic analysis was performed to reveal comprehensive molecular insights into hypothalamic hamartoma (HH). METHODS: Thirty-eight individuals with HH were investigated by whole exome sequencing, target capture-based deep sequencing, or single nucleotide polymorphism (SNP) array using DNA extracted from blood leukocytes or HH samples. RESULTS: We identified a germline variant of KIAA0556, which encodes a ciliary protein, and 2 somatic variants of PTPN11, which forms part of the RAS/mitogen-activated protein kinase (MAPK) pathway, as well as variants in known genes associated with HH. An SNP array identified (among 3 patients) one germline copy-neutral loss of heterozygosity (cnLOH) at 6p22.3-p21.31 and 2 somatic cnLOH; one at 11q12.2-q25 that included DYNC2H1, which encodes a ciliary motor protein, and the other at 17p13.3-p11.2. A germline heterozygous variant and an identical somatic variant of DYNC2H1 arising from cnLOH at 11q12.2-q25 were confirmed in one patient (whose HH tissue, therefore, contains biallelic variants of DYNC2H1). Furthermore, a combination of a germline and a somatic DYNC2H1 variant was detected in another patient. CONCLUSIONS: Overall, our cohort identified germline/somatic alterations in 34% (13/38) of patients with HH. Disruption of the Shh signaling pathway associated with cilia or the RAS/MAPK pathway may lead to the development of HH.

11.
Nat Commun ; 10(1): 2884, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253780

RESUMO

Hereditary retinal degenerations (HRDs) are Mendelian diseases characterized by progressive blindness and caused by ultra-rare mutations. In a genomic screen of 331 unrelated Japanese patients, we identify a disruptive Alu insertion and a nonsense variant (p.Arg1933*) in the ciliary gene RP1, neither of which are rare alleles in Japan. p.Arg1933* is almost polymorphic (frequency = 0.6%, amongst 12,000 individuals), does not cause disease in homozygosis or heterozygosis, and yet is significantly enriched in HRD patients (frequency = 2.1%, i.e., a 3.5-fold enrichment; p-value = 9.2 × 10-5). Familial co-segregation and association analyses show that p.Arg1933* can act as a Mendelian mutation in trans with the Alu insertion, but might also associate with disease in combination with two alleles in the EYS gene in a non-Mendelian pattern of heredity. Our results suggest that rare conditions such as HRDs can be paradoxically determined by relatively common variants, following a quasi-Mendelian model linking monogenic and complex inheritance.


Assuntos
Ciliopatias/genética , Proteínas do Olho/genética , Predisposição Genética para Doença , Doenças Retinianas/genética , Elementos Alu/genética , Grupo com Ancestrais do Continente Asiático/genética , Genômica , Humanos , Japão , Mutação , Linhagem
12.
J Hum Genet ; 64(9): 955-960, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31213653

RESUMO

Identification of genetic causes of primary monogenic immunodeficiencies would strengthen the current understanding of their immunopathology. Pathogenic variants in genes in association with tumor necrosis factor α (TNFα) signaling, including OTULIN, TNFAIP3, RBCK1, and RNF31 cause human congenital autoinflammatory diseases with/without immunodeficiency. RIPK1, encoding a receptor interacting serine/threonine kinase 1, is present in protein complexes mediating signal transduction including TNF receptor 1. Biallelic loss-of-function variants in RIPK1 were recently reported in individuals with primary immunodeficiency with intestinal bowel disease and arthritis. Here, we report a novel homozygous RIPK1 variant in a boy with immunodeficiency and chronic enteropathy. Our patient exhibited severe motor delay and mild intellectual disability, which were previously unknown. The present results are expected to deepen the current understanding of clinical features based on RIPK1 abnormalities.

13.
Arthritis Res Ther ; 21(1): 137, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164164

RESUMO

BACKGROUND: Haploinsufficiency of A20 (HA20) is caused by loss-of-function TNFAIP3 variants. Phenotypic and genetic features of HA20 remain uncertain; therefore, the clinical distinction between HA20 and Behçet's disease (BD) requires clarification. METHODS: We have collected 12 Japanese BD-like families. Probands of these families were analyzed by whole exome sequencing (WES) and subsequent Sanger sequencing. Clinical features were compared between 54 HA20 patients (including previously reported and new cases) and 520 Japanese BD patients. RESULTS: We identified c.1434C>A:p.(Cys478*) in one family and a 236 kb deletion at 6q23.3 containing TNFAIP3 in another family. Four HA20 patients in the two families presented with childhood-onset recurrent oral and genital ulcers and were initially diagnosed and treated as BD. Consistent with the clinical features of HA20, recurrent, refractory fever attacks (three of four patients), and digestive ulcers (two of the four patients) were observed. A comparison of clinical features between HA20 patients and cohorts of BD patients revealed several critical features specific to HA20. These were early-onset, familial occurrence, recurrent fever attacks, gastrointestinal involvement, and infrequent ocular involvement. CONCLUSIONS: We identified a novel nonsense variant and deletion of the entire TNFAIP3 gene in two unrelated Japanese HA20 families. Genetic screening of TNFAIP3 should be considered for familial BD-like patients with early-onset recurrent fevers.

14.
Neurobiol Dis ; 130: 104516, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31229688

RESUMO

Spinocerebellar ataxia 42 (SCA42) is a neurodegenerative disorder recently shown to be caused by c.5144G > A (p.Arg1715His) mutation in CACNA1G, which encodes the T-type voltage-gated calcium channel CaV3.1. Here, we describe a large Japanese family with SCA42. Postmortem pathological examination revealed severe cerebellar degeneration with prominent Purkinje cell loss without ubiquitin accumulation in an SCA42 patient. To determine whether this mutation causes ataxic symptoms and neurodegeneration, we generated knock-in mice harboring c.5168G > A (p.Arg1723His) mutation in Cacna1g, corresponding to the mutation identified in the SCA42 family. Both heterozygous and homozygous mutants developed an ataxic phenotype from the age of 11-20 weeks and showed Purkinje cell loss at 50 weeks old. Degenerative change of Purkinje cells and atrophic thinning of the molecular layer were conspicuous in homozygous knock-in mice. Electrophysiological analysis of Purkinje cells using acute cerebellar slices from young mice showed that the point mutation altered the voltage dependence of CaV3.1 channel activation and reduced the rebound action potentials after hyperpolarization, although it did not significantly affect the basic properties of synaptic transmission onto Purkinje cells. Finally, we revealed that the resonance of membrane potential of neurons in the inferior olivary nucleus was decreased in knock-in mice, which indicates that p.Arg1723His CaV3.1 mutation affects climbing fiber signaling to Purkinje cells. Altogether, our study shows not only that a point mutation in CACNA1G causes an ataxic phenotype and Purkinje cell degeneration in a mouse model, but also that the electrophysiological abnormalities at an early stage of SCA42 precede Purkinje cell loss.

15.
Intern Med ; 58(18): 2715-2719, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31178479

RESUMO

A 24-year-old Japanese man exhibited slowly progressive gait disturbance from childhood to young adulthood. Physical and physiological examinations showed the involvement of both upper and lower motor neurons, fulfilling the diagnostic criteria for amyotrophic lateral sclerosis (ALS). Mild cognitive impairment and subclinical sensory involvement were also observed. A genetic analysis revealed novel compound heterozygous mutations, c.767C>T (p.Thr256Ile) and c.800A>G (p.Asp267Gly), in the vaccinia-related kinase 1 gene (VRK1). This is the first report of a Japanese patient with a motor neuron disease phenotype caused by VRK1 mutations. This diagnosis should be considered in atypical cases of juvenile-onset and slowly progressive types of motor neuron disease.

16.
Hum Mol Genet ; 28(18): 3113-3125, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31211835

RESUMO

Oculomotor synkinesis is the involuntary movement of the eyes or eyelids with a voluntary attempt at a different movement. The chemokine receptor CXCR4 and its ligand CXCL12 regulate oculomotor nerve development; mice with loss of either molecule have oculomotor synkinesis. In a consanguineous family with congenital ptosis and elevation of the ptotic eyelid with ipsilateral abduction, we identified a co-segregating homozygous missense variant (c.772G>A) in ACKR3, which encodes an atypical chemokine receptor that binds CXCL12 and functions as a scavenger receptor, regulating levels of CXCL12 available for CXCR4 signaling. The mutant protein (p.V258M) is expressed and traffics to the cell surface but has a lower binding affinity for CXCL12. Mice with loss of Ackr3 have variable phenotypes that include misrouting of the oculomotor and abducens nerves. All embryos show oculomotor nerve misrouting, ranging from complete misprojection in the midbrain, to aberrant peripheral branching, to a thin nerve, which aberrantly innervates the lateral rectus (as seen in Duane syndrome). The abducens nerve phenotype ranges from complete absence, to aberrant projections within the orbit, to a normal trajectory. Loss of ACKR3 in the midbrain leads to downregulation of CXCR4 protein, consistent with reports that excess CXCL12 causes ligand-induced degradation of CXCR4. Correspondingly, excess CXCL12 applied to ex vivo oculomotor slices causes axon misrouting, similar to inhibition of CXCR4. Thus, ACKR3, through its regulation of CXCL12 levels, is an important regulator of axon guidance in the oculomotor system; complete loss causes oculomotor synkinesis in mice, while reduced function causes oculomotor synkinesis in humans.

17.
J Hum Genet ; 64(8): 821-827, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31110234

RESUMO

We identified a de novo frameshift variant (NM_015048.1:c.5644_5647del:p.(Ile1882Serfs*118)) in the last exon of SETD1B in a Japanese patient with autistic behavior, developmental delay, intellectual disability, and myoclonic seizures. This variant is predicted to disrupt a well-conserved carboxyl-terminus SET domain, which is known to modulate gene activities and/or chromatin structure. Previously, two de novo missense mutations in SETD1B were reported in two patients with epilepsy. All three patients including the current patient share similar clinical features. Herein, we report a first epilepsy patient with a frameshift variant in SETD1B, emphasizing a possible pathomechanistic association of SETD1B abnormality with neurodevelopmental delay with epilepsy.

18.
Am J Med Genet A ; 179(7): 1126-1138, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31058441

RESUMO

CHOPS syndrome is a multisystem disorder caused by missense mutations in AFF4. Previously, we reported three individuals whose primary phenotype included cognitive impairment and coarse facies, heart defects, obesity, pulmonary involvement, and short stature. This syndrome overlaps phenotypically with Cornelia de Lange syndrome, but presents distinct differences including facial features, pulmonary involvement, and obesity. Here, we provide clinical descriptions of an additional eight individuals with CHOPS syndrome, as well as neurocognitive analysis of three individuals. All 11 individuals presented with features reminiscent of Cornelia de Lange syndrome such as synophrys, upturned nasal tip, arched eyebrows, and long eyelashes. All 11 individuals had short stature and obesity. Congenital heart disease and pulmonary involvement were common, and those were seen in about 70% of individuals with CHOPS syndrome. Skeletal abnormalities are also common, and those include abnormal shape of vertebral bodies, hypoplastic long bones, and low bone mineral density. Our observation indicates that obesity, pulmonary involvement, skeletal findings are the most notable features distinguishing CHOPS syndrome from Cornelia de Lange syndrome. In fact, two out of eight of our newly identified patients were found to have AFF4 mutations by targeted AFF4 mutational analysis rather than exome sequencing. These phenotypic findings establish CHOPS syndrome as a distinct, clinically recognizable disorder. Additionally, we report three novel missense mutations causative for CHOPS syndrome that lie within the highly conserved, 14 amino acid sequence of the ALF homology domain of the AFF4 gene, emphasizing the critical functional role of this region in human development.

19.
Ann Neurol ; 85(6): 927-933, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30945334

RESUMO

c-Jun-amino-terminal kinase-interacting protein 3 (JIP3), encoded by MAPK8IP3, is an adaptor protein of the kinesin-1 complex and essential for axonal transport in neurons. However, an association between MAPK8IP3 variants and human disease has not been established. We identified 5 individuals from four families with recurrent de novo variants c.1732C>T (p.Arg578Cys) and c.3436C>T (p.Arg1146Cys) in MAPK8IP3. The core phenotype includes spastic diplegia, intellectual disability, cerebral atrophy, and corpus callosum hypoplasia. Zebrafish embryos overexpressing human mutant JIP3 showed axon varicosities of the posterior lateral line nerve, suggesting an adverse effect on the developing axons. Our results suggest that MAPK8IP3 variants cause a neurodevelopmental disease. ANN NEUROL 2019;85:927-933.

20.
Am J Hum Genet ; 104(5): 925-935, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-30982609

RESUMO

Colony stimulating factor 1 receptor (CSF1R) plays key roles in regulating development and function of the monocyte/macrophage lineage, including microglia and osteoclasts. Mono-allelic mutations of CSF1R are known to cause hereditary diffuse leukoencephalopathy with spheroids (HDLS), an adult-onset progressive neurodegenerative disorder. Here, we report seven affected individuals from three unrelated families who had bi-allelic CSF1R mutations. In addition to early-onset HDLS-like neurological disorders, they had brain malformations and skeletal dysplasia compatible to dysosteosclerosis (DOS) or Pyle disease. We identified five CSF1R mutations that were homozygous or compound heterozygous in these affected individuals. Two of them were deep intronic mutations resulting in abnormal inclusion of intron sequences in the mRNA. Compared with Csf1r-null mice, the skeletal and neural phenotypes of the affected individuals appeared milder and variable, suggesting that at least one of the mutations in each affected individual is hypomorphic. Our results characterized a unique human skeletal phenotype caused by CSF1R deficiency and implied that bi-allelic CSF1R mutations cause a spectrum of neurological and skeletal disorders, probably depending on the residual CSF1R function.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA