RESUMEN
Biallelic pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause a pleiotropic multisystem disorder. Three clinical subgroups have been defined correlating with the localisation of pathogenic variants in the NBAS gene: variants affecting the C-terminal region of NBAS result in SOPH syndrome (short stature, optic atrophy, Pelger-Huët anomaly), variants affecting the Sec 39 domain are associated with infantile liver failure syndrome type 2 (ILFS2) and variants affecting the ß-propeller domain give rise to a combined phenotype. However, there is still unexplained phenotypic diversity across the three subgroups, challenging the current concept of genotype-phenotype correlations in NBAS-associated disease. Therefore, besides examining the genetic influence, we aim to elucidate the potential impact of pre-symptomatic diagnosis, emergency management and other modifying variables on the clinical phenotype. We investigated genotype-phenotype correlations in individuals sharing the same genotypes (n = 30 individuals), and in those sharing the same missense variants with a loss-of-function variant in trans (n = 38 individuals). Effects of a pre-symptomatic diagnosis and emergency management on the severity of acute liver failure (ALF) episodes also were analysed, comparing liver function tests (ALAT, ASAT, INR) and mortality. A strong genotype-phenotype correlation was demonstrated in individuals sharing the same genotype; this was especially true for the ILFS2 subgroup. Genotype-phenotype correlation in patients sharing only one missense variant was still high, though at a lower level. Pre-symptomatic diagnosis in combination with an emergency management protocol leads to a trend of reduced severity of ALF. High genetic impact on clinical phenotype in NBAS-associated disease facilitates monitoring and management of affected patients sharing the same genotype. Pre-symptomatic diagnosis and an emergency management protocol do not prevent ALF but may reduce its clinical severity.
Asunto(s)
Fallo Hepático Agudo , Neuroblastoma , Anomalía de Pelger-Huët , Humanos , Fenotipo , Anomalía de Pelger-Huët/complicaciones , Anomalía de Pelger-Huët/genética , Anomalía de Pelger-Huët/patología , Fallo Hepático Agudo/genética , Mutación Missense , Neuroblastoma/complicacionesRESUMEN
Pelger-Huët anomaly (PHA) in humans is an autosomal dominant hematological phenotype without major clinical consequences. PHA involves a characteristic hyposegmentation of granulocytes (HG). Human PHA is caused by heterozygous loss of function variants in the LBR gene encoding lamin receptor B. Bi-allelic variants and complete deficiency of LBR cause the much more severe Greenberg skeletal dysplasia which is lethal in utero and characterized by massive skeletal malformation and gross fetal hydrops. HG phenotypes have also been described in domestic animals and homology to human PHA has been claimed in the literature. We studied a litter of Australian Shepherd Dogs with four stillborn puppies in which both parents had an HG phenotype. Linkage analysis excluded LBR as responsible gene for the stillborn puppies. We then investigated the HG phenotype in Australian Shepherd Dogs independently of the prenatal lethality. Genome-wide association mapped the HG locus to chromosome 27 and established an autosomal recessive mode of inheritance. Whole genome sequencing identified a splice site variant in LMBR1L, c.191+1G>A, as most likely causal variant for the HG phenotype. The mutant allele abrogates the expression of the longer X2 isoform but does not affect transcripts encoding the shorter X1 isoform of the LMBR1L protein. The homozygous mutant LMBR1L genotype associated with HG is common in Australian Shepherd Dogs and was found in 39 of 300 genotyped dogs (13%). Our results point to a previously unsuspected function of LMBR1L in the myeloid lineage of leukocytes.
Asunto(s)
Estudio de Asociación del Genoma Completo , Anomalía de Pelger-Huët , Femenino , Embarazo , Perros , Humanos , Animales , Receptores Citoplasmáticos y Nucleares/genética , Australia , Granulocitos , Genotipo , Anomalía de Pelger-Huët/genética , Lamina Tipo B/genética , Receptores de Superficie Celular/genéticaRESUMEN
Objective: To investigate the clinical efficacy of liver transplantation in the treatment of acute liver in children with NBAS gene deficiency disease and their outcome. Methods: This retrospective study enrolled children with NBAS gene deficiency who were admitted to the Children's Hospital of Fudan University for liver transplantation from January 2013 to June 2022. The clinical data were collected and analyzed. Medical literature published before June 2022 was searched with the keywords of "NBAS" "neuroblastoma amplified sequence recurrent" "acute liver failure" "SOPH syndrome" "short stature with optic nerve atrophy" "Pelger-Huët anomaly" in PubMed, China National Knowledge Infrastructure and Wanfang database. Results: Liver transplantation was performed in 3 patients (2 males and 1 female) with NBAS deficiency. All patients presented with fever-triggered recurrent acute liver failure. The genetic detection found compound heterozygous NBAS gene pathogenic variants in them. The total episodes of acute liver failure before liver transplantation were 11, 2, and 4 respectively, and the age at liver transplantation was 3.5, 2.3, and 2.0 years respectively. During liver transplantation, patient 1 was in the convalescent phase of acute liver failure, patient 2 was in the acute phase, presenting with hepatic encephalopathy (grade V) and respiratory failure, and patient 3 was considered to be in the acute phase. After liver transplantation, patient 1 recovered normal liver function within 1 month and had no liver transplantation-related complications. Patient 2 had secondary epilepsy, intellectual disability, movement disorder, and transiently elevated transaminases. Patient 3 died of severe infection within 1 month. There was no literature in Chinese, 6 in English, 8 NBAS-deficient patients who were treated with liver transplantation. Total 11 patients presented with fever-triggered recurrent acute liver failure. Their age at liver transplantation ranged from 0.9 to 5.0 years. Postoperative complications occurred in 3 patients. Until the last visit, they were followed up for 0.7 to 14.0 years. Total 2 patients died and the 9 surviving patients did not develop acute liver failure. Conclusions: Liver transplantation is effective for the treatment of acute liver failure associated with NBAS gene disease. However, postoperative complications of liver transplantation may occur. The timing of liver transplantation still needs further research.
Asunto(s)
Fallo Hepático Agudo , Atrofia Óptica , Anomalía de Pelger-Huët , Niño , Masculino , Humanos , Femenino , Lactante , Preescolar , Estudios Retrospectivos , Proteínas de Neoplasias/genética , Atrofia Óptica/genética , Anomalía de Pelger-Huët/genética , Fallo Hepático Agudo/genética , Fallo Hepático Agudo/cirugía , Fallo Hepático Agudo/complicacionesRESUMEN
BACKGROUND: Biallelic pathogenic variants in the neuroblastoma-amplified sequence (NBAS) gene manifest in a broad spectrum of disorders, including, but not limited to recurrent acute liver failure, skeletal dysmorphism, susceptibility to infections, and SOPH syndrome with its cardinal symptoms of short stature, optic atrophy, and Pelger-Huët anomaly. We aimed to present clinical and genetic characteristics of two sisters (20 and 15 years old) who were diagnosed with optic atrophy and cone dystrophy in childhood. Genome sequencing revealed two novel variants in NBAS in compound heterozygous state in both sisters, namely a 1-bp deletion predicted to result in a premature termination codon (c.5104del; p.(Met1702*)), and a non-canonical splice site variant of unclear significance (c.886-5T>A; p.?). RESULTS: Clinical examination and history revealed cone dystrophy, optic atrophy, and Pelger-Huët anomaly, but no short stature, recurrent acute liver failure, or susceptibility to infections. RNA analysis revealed that the c.886-5T>A variant results in two aberrant transcripts that are predicted to lead to in frame amino acid changes in the ß-propeller region of the protein. CONCLUSION: We hypothesize that the phenotype of our subjects, which appears to be at the end of the spectrum of NBAS-related disorders, could be explained by residual protein function mediated by the non-canonical splice site variant c.886-5T>A. Our study contributes to the existing knowledge on the genotypic and phenotypic spectrum of NBAS-related disorders.
Asunto(s)
Distrofia del Cono , Enanismo , Fallo Hepático Agudo , Neuroblastoma , Atrofia Óptica , Anomalía de Pelger-Huët , Humanos , Anomalía de Pelger-Huët/diagnóstico , Anomalía de Pelger-Huët/genética , Anomalía de Pelger-Huët/patología , Atrofia Óptica/genética , Fallo Hepático Agudo/diagnóstico , Fallo Hepático Agudo/genética , Enanismo/genética , FenotipoRESUMEN
Objective: To investigate the clinical efficacy of liver transplantation in the treatment of acute liver in children with NBAS gene deficiency disease and their outcome. Methods: This retrospective study enrolled children with NBAS gene deficiency who were admitted to the Children's Hospital of Fudan University for liver transplantation from January 2013 to June 2022. The clinical data were collected and analyzed. Medical literature published before June 2022 was searched with the keywords of "NBAS" "neuroblastoma amplified sequence recurrent" "acute liver failure" "SOPH syndrome" "short stature with optic nerve atrophy" "Pelger-Huët anomaly" in PubMed, China National Knowledge Infrastructure and Wanfang database. Results: Liver transplantation was performed in 3 patients (2 males and 1 female) with NBAS deficiency. All patients presented with fever-triggered recurrent acute liver failure. The genetic detection found compound heterozygous NBAS gene pathogenic variants in them. The total episodes of acute liver failure before liver transplantation were 11, 2, and 4 respectively, and the age at liver transplantation was 3.5, 2.3, and 2.0 years respectively. During liver transplantation, patient 1 was in the convalescent phase of acute liver failure, patient 2 was in the acute phase, presenting with hepatic encephalopathy (grade V) and respiratory failure, and patient 3 was considered to be in the acute phase. After liver transplantation, patient 1 recovered normal liver function within 1 month and had no liver transplantation-related complications. Patient 2 had secondary epilepsy, intellectual disability, movement disorder, and transiently elevated transaminases. Patient 3 died of severe infection within 1 month. There was no literature in Chinese, 6 in English, 8 NBAS-deficient patients who were treated with liver transplantation. Total 11 patients presented with fever-triggered recurrent acute liver failure. Their age at liver transplantation ranged from 0.9 to 5.0 years. Postoperative complications occurred in 3 patients. Until the last visit, they were followed up for 0.7 to 14.0 years. Total 2 patients died and the 9 surviving patients did not develop acute liver failure. Conclusions: Liver transplantation is effective for the treatment of acute liver failure associated with NBAS gene disease. However, postoperative complications of liver transplantation may occur. The timing of liver transplantation still needs further research.
Asunto(s)
Niño , Masculino , Humanos , Femenino , Lactante , Preescolar , Estudios Retrospectivos , Proteínas de Neoplasias/genética , Atrofia Óptica/genética , Anomalía de Pelger-Huët/genética , Fallo Hepático Agudo/complicacionesRESUMEN
The transmembrane protein TMEM147 has a dual function: first at the nuclear envelope, where it anchors lamin B receptor (LBR) to the inner membrane, and second at the endoplasmic reticulum (ER), where it facilitates the translation of nascent polypeptides within the ribosome-bound TMCO1 translocon complex. Through international data sharing, we identified 23 individuals from 15 unrelated families with bi-allelic TMEM147 loss-of-function variants, including splice-site, nonsense, frameshift, and missense variants. These affected children displayed congruent clinical features including coarse facies, developmental delay, intellectual disability, and behavioral problems. In silico structural analyses predicted disruptive consequences of the identified amino acid substitutions on translocon complex assembly and/or function, and in vitro analyses documented accelerated protein degradation via the autophagy-lysosomal-mediated pathway. Furthermore, TMEM147-deficient cells showed CKAP4 (CLIMP-63) and RTN4 (NOGO) upregulation with a concomitant reorientation of the ER, which was also witnessed in primary fibroblast cell culture. LBR mislocalization and nuclear segmentation was observed in primary fibroblast cells. Abnormal nuclear segmentation and chromatin compaction were also observed in approximately 20% of neutrophils, indicating the presence of a pseudo-Pelger-Huët anomaly. Finally, co-expression analysis revealed significant correlation with neurodevelopmental genes in the brain, further supporting a role of TMEM147 in neurodevelopment. Our findings provide clinical, genetic, and functional evidence that bi-allelic loss-of-function variants in TMEM147 cause syndromic intellectual disability due to ER-translocon and nuclear organization dysfunction.
Asunto(s)
Discapacidad Intelectual , Anomalías Musculoesqueléticas , Anomalía de Pelger-Huët , Núcleo Celular/genética , Niño , Cromatina , Humanos , Discapacidad Intelectual/genética , Pérdida de Heterocigocidad , Anomalía de Pelger-Huët/genéticaRESUMEN
The characteristic lobulated nuclear morphology of granulocytes is partially determined by composition of nuclear envelope proteins. Abnormal nuclear morphology is primarily observed as an increased number of hypolobulated immature neutrophils, called band cells, during infection or in rare envelopathies like Pelger-Huët anomaly. To search for sequence variants affecting nuclear morphology of granulocytes, we performed a genome-wide association study using band neutrophil fraction from 88,101 Icelanders. We describe 13 sequence variants affecting band neutrophil fraction at nine loci. Five of the variants are at the Lamin B receptor (LBR) locus, encoding an inner nuclear membrane protein. Mutations in LBR are linked to Pelger-Huët anomaly. In addition, we identify cosegregation of a rare stop-gain sequence variant in LBR and Pelger Huët anomaly in an Icelandic eight generation pedigree, initially reported in 1963. Two of the other loci include genes which, like LBR, play a role in the nuclear membrane function and integrity. These GWAS results highlight the role proteins of the inner nuclear membrane have as important for neutrophil nuclear morphology.
Asunto(s)
Anomalía de Pelger-Huët , Estudio de Asociación del Genoma Completo , Granulocitos/metabolismo , Humanos , Islandia , Neutrófilos/metabolismo , Anomalía de Pelger-Huët/genéticaRESUMEN
In this issue of Cell Stem Cell, Reilly et al. propose loss of LMNB1, the gene encoding lamin B1, often deleted in MDS/AML, as a novel genetic basis for the abnormal nuclear shape of neutrophils (known as acquired Pelger-Huët anomaly) and a cause of HSPC fate alterations promoting malignancy.
Asunto(s)
Leucemia Mieloide Aguda , Anomalía de Pelger-Huët , Núcleo Celular , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Neutrófilos/patología , Anomalía de Pelger-Huët/genética , Anomalía de Pelger-Huët/patologíaRESUMEN
Abnormal nuclear morphology is a hallmark of malignant cells widely used in cancer diagnosis. Pelger-Huët anomaly (PHA) is a common abnormality of neutrophil nuclear morphology of unknown molecular etiology in myeloid neoplasms (MNs). We show that loss of nuclear lamin B1 (LMNB1) encoded on chromosome 5q, which is frequently deleted in MNs, induces defects in nuclear morphology and human hematopoietic stem cell (HSC) function associated with malignancy. LMNB1 deficiency alters genome organization inducing in vitro and in vivo expansion of HSCs, myeloid-biased differentiation with impaired lymphoid commitment, and genome instability due to defective DNA damage repair. Nuclear dysmorphology of neutrophils in patients with MNs is associated with 5q deletions spanning the LMNB1 locus, and lamin B1 loss is both necessary and sufficient to cause PHA in normal and 5q-deleted neutrophils. LMNB1 loss thus causes acquired PHA and links abnormal nuclear morphology with HSCs and progenitor cell fate determination via genome organization.
Asunto(s)
Trastornos Mieloproliferativos , Neoplasias , Anomalía de Pelger-Huët , Núcleo Celular , Células Madre Hematopoyéticas/patología , Humanos , Lamina Tipo B/genética , Anomalía de Pelger-Huët/genética , Anomalía de Pelger-Huët/patologíaRESUMEN
The lamin-B receptor (LBR) encodes a dual-functioning inner nuclear membrane protein essential for cholesterol biosynthesis and chromatin organization. LBR pathogenic variants cause distinct phenotypes due to the dual function of LBR, including Pelger-Huët anomaly (PHA), PHA with mild skeletal anomalies (PHASK; MIM# 618019), LBR-related regressive type of spondylometaphyseal dysplasia (LBR-R-SMD), Greenberg dysplasia (MIM# 215140). We here report the first case with radiological manifestations of LBR-R-SMD in the fetal period, and milder skeletal findings in the similarly affected father. Direct sequencing of LBR revealed homozygous c.1534C>T (p.Arg512Trp) in exon 12 in both affected individuals. Our report further refines the early phenotype in LBR-R-SMD, and demonstrates that the p.Arg512Trp mutation is associated with PHA. We propose that LBR-R-SMD should be considered as a differential diagnosis in pregnancies with sonographic evidence of short and bowed tubular bones with narrow thorax. Evaluating peripheral blood smears of expectant parents for the presence of PHA may lead to a clinical diagnosis, allowing for comprehensive prenatal genetic counseling.
Asunto(s)
Osteocondrodisplasias , Anomalía de Pelger-Huët , Femenino , Humanos , Laminas/genética , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Osteocondrodisplasias/patología , Linaje , Anomalía de Pelger-Huët/genética , EmbarazoRESUMEN
Mutations in the gene encoding Lamin B receptor (LBR), a nuclear-membrane protein with sterol reductase activity, have been linked to rare human disorders. Phenotypes range from a benign blood disorder, such as Pelger-Huet anomaly (PHA), affecting the morphology and chromatin organization of white blood cells, to embryonic lethality as for Greenberg dysplasia (GRBGD). Existing PHA mouse models do not fully recapitulate the human phenotypes, hindering efforts to understand the molecular etiology of this disorder. Here we show, using CRISPR/Cas-9 gene editing technology, that a 236bp N-terminal deletion in the mouse Lbr gene, generating a protein missing the N-terminal domains of LBR, presents a superior model of human PHA. Further, we address recent reports of a link between Lbr and defects in X chromosome inactivation (XCI) and show that our mouse mutant displays minor X chromosome inactivation defects that do not lead to any overt phenotypes in vivo. We suggest that our N-terminal deletion model provides a valuable pre-clinical tool to the research community and will aid in further understanding the etiology of PHA and the diverse functions of LBR.
Asunto(s)
Anomalía de Pelger-Huët/genética , Receptores Citoplasmáticos y Nucleares/genética , Inactivación del Cromosoma X/genética , Animales , Ratones , Ratones Noqueados , Fenotipo , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptor de Lamina BRESUMEN
Biallelic neuroblastoma ampliï¬ed sequence (NBAS) gene mutations have recently been identified to cause a reduction in its protein expression and a broad phenotypic spectrum, from isolated short stature, optic nerve atrophy, and Pelger-Huët anomaly (SOPH) syndrome or infantile liver failure syndrome 2 to a combined, multi-systemic disease including skeletal dysplasia and immunological and neurological abnormalities. Herein, we report a 34-year-old patient with a range of phenotypes for NBAS deficiency due to compound heterozygous variants; one is a SOPH-specific variant, p.Arg1914His, and the other is a novel splice site variant, c.6433-2A>G. The patient experienced recurrent acute liver failure until early childhood. Hypogammaglobulinemia, a decrease in natural killer cells, and optic nerve atrophy were evident from infancy to childhood. In adulthood, the patient exhibited novel phenotypic features such as hepatic cirrhosis complicated by portal hypertension and autoimmune hemolytic anemia. The patient also suffered from childhood-onset insulin-requiring diabetes with progressive beta cell dysfunction. The patient had severe short stature and exhibited dysmorphic features compatible with SOPH, intellectual disability, and epilepsy. NBAS protein expression in the patient's fibroblasts was severely low. RNA expression analysis for the c.6433-2A>G variant showed that this variant activated two cryptic splice sites in intron 49 and exon 50, for which the predicted consequences at the protein level were an in-frame deletion/insertion, p.(Ile2199_Asn2202delins16), and a premature termination codon, p.(Ile2199Tyrfs*17), respectively. These findings indicate that NBAS deficiency is a multi-systemic progressive disease. The results of this study extend the spectrum of clinical and genetic findings related to NBAS deficiency.
Asunto(s)
Enanismo/genética , Cirrosis Hepática/genética , Proteínas de Neoplasias/genética , Atrofias Ópticas Hereditarias/genética , Anomalía de Pelger-Huët/genética , Fenotipo , Adulto , Células Cultivadas , Enanismo/patología , Humanos , Cirrosis Hepática/patología , Masculino , Mutación , Proteínas de Neoplasias/deficiencia , Proteínas de Neoplasias/metabolismo , Atrofias Ópticas Hereditarias/patología , Anomalía de Pelger-Huët/patologíaRESUMEN
Lamin B receptor, a member of the sterol reductase family, is an inner nuclear membrane protein which binds lamin B proteins and is involved in the organization of heterochromatin. Mutations in LBR have been associated with a variety of disorders, such as Pelger-Huët anomaly, a benign abnormality affecting neutrophils, and Greenberg Dysplasia, a lethal condition in the perinatal period. We identified a homozygous LBR missense mutation (NM_002296.4: c.1366C > G, p.(Leu456Val)) in two adult sisters with a Lamin B receptor-related disorder associated with a skeletal dysplasia milder than Greenberg Dysplasia. Individual 1 has short stature with short limbs (mostly rhizomelic for the upper extremities, and mesomelic for the lower extremities), limited elbow extension. She required Achilles tenotomy, and does not have facial dysmorphisms. Individual 2 has similar skeletal features, but also has bowed femurs, osteopenia, spastic paraplegia of the lower limbs, equinovarus feet, a single kidney, neurogenic bladder, obstructive hydronephrosis, scoliosis and syndactyly of the toes. This report provides additional evidence of variability for Lamin B receptor-related disorders associated with a non-lethal skeletal dysplasia without Pelger-Huët anomaly. We describe a novel pathogenic variant that has not been previously associated with disease and demonstrate the effect of this variant on sterol C14-reductase activity.
Asunto(s)
Osteocondrodisplasias , Anomalía de Pelger-Huët , Adulto , Femenino , Homocigoto , Humanos , Osteocondrodisplasias/genética , Anomalía de Pelger-Huët/genética , Embarazo , Receptores Citoplasmáticos y Nucleares , Receptor de Lamina BAsunto(s)
Enfermedad de Crohn/patología , Hallazgos Incidentales , Anomalía de Pelger-Huët/diagnóstico , Enfermedad Aguda , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/terapia , Femenino , Heterocigoto , Hospitalización , Humanos , Persona de Mediana Edad , Mutación , Anomalía de Pelger-Huët/complicaciones , Anomalía de Pelger-Huët/genética , Anomalía de Pelger-Huët/terapia , Receptores Citoplasmáticos y Nucleares/genética , Receptor de Lamina BRESUMEN
Autosomal recessive SOPH syndrome was first described in the Yakuts population of Asia by Maksimova et al. in 2010. It arises from biallelic pathogenic variants in the NBAS gene and is characterized by severe postnatal growth retardation, senile facial appearance, small hands and feet, optic atrophy with loss of visual acuity and color vision, and normal intelligence (OMIM #614800). The presence of Pelger-Hüet anomaly in this disorder led to its name as an acronym for Short stature, Optic nerve atrophy, and Pelger-Hüet anomaly. Recent publications have further contributed to the characterization of this syndrome through additional phenotype-genotype correlations. We review the clinical features described in these publications and report on a 27-year-old woman with dwarfism with osteolysis and multiple skeletal problems, minor anomalies, immunodeficiency, diabetes mellitus, and multiple secondary medical problems. Her condition was considered an unknown autosomal recessive disorder for many years until exome sequencing provided the diagnosis by revealing a founder disease-causing variant that was compound heterozygous with a novel pathogenic variant in NBAS. Based on the major clinical features of this individual and others reported earlier, a revision of the acronym is warranted to facilitate clinical recognition.
Asunto(s)
Enanismo/genética , Síndromes de Inmunodeficiencia/genética , Proteínas de Neoplasias/genética , Anomalía de Pelger-Huët/genética , Adulto , Enanismo/complicaciones , Enanismo/patología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Síndromes de Inmunodeficiencia/complicaciones , Síndromes de Inmunodeficiencia/patología , Mutación/genética , Atrofia Óptica/genética , Atrofia Óptica/patología , Anomalía de Pelger-Huët/complicaciones , Anomalía de Pelger-Huët/patología , Secuenciación del ExomaRESUMEN
OBJECTIVE: To detect mutation of LBR gene in a pedigree affected with Pelger-HuÑt anomaly (PHA) and to explore its clinical characteristics. METHODS: Genomic DNA was extracted from the pedigree and healthy controls. The 14 exons of the LBR gene were subjected to PCR amplification and Sanger sequencing. Suspected mutations were verified in other family members and 100 healthy controls. Polyphen-2 and SIFT software were used to predict the effect of the mutation, and Swiss-model software was used to simulate the protein structure. RESULTS: Three patients were found to carry a c.893G>A mutation in exon 8 of the LBR gene, which resulted in substitution of the 298th amino acid residue glycine by glutamic acid (p.Gly298Glu). The same mutation was not found in healthy family members and 100 healthy controls. The mutation was predicted to be damaging. Bioinformatic simulation showed the mutation has altered the 3D structure of the LBR protein. CONCLUSION: The c.893G>A (p.Gly298Glu) mutation in the LBR gene probably underlies the PHA in this pedigree and has enriched the spectrum of LBR gene mutations.
Asunto(s)
Anomalía de Pelger-Huët/genética , Receptores Citoplasmáticos y Nucleares/genética , Estudios de Casos y Controles , Análisis Mutacional de ADN , Exones , Humanos , Mutación , Linaje , Reacción en Cadena de la Polimerasa , Receptor de Lamina BRESUMEN
Individuals affected with autosomal recessive cutis laxa type 2B and 3 usually show translucent skin with visible veins and abnormal elastic fibers, intrauterine and/or postnatal growth restriction and a typical triangular facial gestalt. Here we describe three unrelated individuals in whom such a cutis laxa syndrome was suspected, especially after electron microscopy revealed immature and less dense dermal elastic fibers in one of them. However, one of these children also displayed optic atrophy and two hypogammaglobulinemia. All had elevated liver enzymes and acute liver failure during febrile episodes leading to early demise in two of them. The only surviving patient had been treated with immunoglobulins. Through exome sequencing we identified mutations in NBAS, coding for a protein involved in Golgi-to-ER transport. NBAS deficiency causes several rare conditions ranging from isolated recurrent acute liver failure to a multisystem disorder mainly characterized by short stature, optic nerve atrophy and Pelger-Huët anomaly (SOPH). Since we subsequently verified Pelger-Huët anomaly in two of the patients the diagnosis SOPH syndrome was unequivocally proven. Our data show that SOPH syndrome can be regarded as a differential diagnosis for the progeroid forms of cutis laxa in early infancy and that possibly treatment of the hypogammaglobulinemia can be of high relevance for the prognosis.
Asunto(s)
Trastornos del Crecimiento/diagnóstico , Proteínas de Neoplasias/genética , Enfermedades del Nervio Óptico/diagnóstico , Anomalía de Pelger-Huët/diagnóstico , Agammaglobulinemia/sangre , Agammaglobulinemia/fisiopatología , Cutis Laxo/diagnóstico , Cutis Laxo/genética , Cutis Laxo/patología , Diagnóstico Diferencial , Tejido Elástico/ultraestructura , Trastornos del Crecimiento/genética , Trastornos del Crecimiento/patología , Humanos , Lactante , Hígado/enzimología , Hígado/patología , Masculino , Enfermedades del Nervio Óptico/genética , Enfermedades del Nervio Óptico/patología , Anomalía de Pelger-Huët/genética , Anomalía de Pelger-Huët/patología , Progeria/diagnóstico , Progeria/genética , Piel/patología , Síndrome , Secuenciación del Exoma , Adulto JovenRESUMEN
Greenberg skeletal dysplasia is an autosomal recessive, perinatal lethal disorder associated with biallelic variants affecting the lamin B receptor (LBR) gene. LBR is also associated with the autosomal recessive anadysplasia-like spondylometaphyseal dysplasia, and the autosomal dominant Pelger-Huët anomaly, a benign laminopathy characterized by anomalies in the nuclear shape of blood granulocytes. The LBR is an inner nuclear membrane protein that binds lamin B proteins (LMNB1 and LMNB2), interacts with chromatin, and exerts a sterol reductase activity. Here, we report on a novel LBR missense variant [c.1379A>G; p.(D460R)], identified by whole exome sequencing and causing Greenberg dysplasia in two fetuses from a consanguineous Moroccan family. We revised published LBR variants to propose a genotype-phenotype correlation in LBR associated diseases. The diverse phenotypes are correlated to the functional domain affected, the heterozygous or homozygous state of the variants, and their different impact on the residual protein function. LBR represents an instructive example of one gene presenting with two different patterns of inheritance and at least three different clinical phenotypes.
Asunto(s)
Secuenciación del Exoma , Osteocondrodisplasias/genética , Anomalía de Pelger-Huët/genética , Receptores Citoplasmáticos y Nucleares/genética , Cromatina/genética , Femenino , Feto/fisiopatología , Estudios de Asociación Genética , Homocigoto , Humanos , Lamina Tipo B/genética , Osteocondrodisplasias/fisiopatología , Anomalía de Pelger-Huët/fisiopatología , Fenotipo , Embarazo , Receptor de Lamina BRESUMEN
BACKGROUND: Short stature with optic atrophy and Pelger-Huet anomaly (SOPH; MIM 614800) syndrome is a genetic disease caused by mutation in the neuroblastoma amplified sequence (NBAS) gene. CASE REPORT: We present a 11-year-old Chinese boy with SOPH syndrome, growth hormone deficiency with a normal bone age. Gene sequencing in the patient revealed a novel compound heterozygous mutation of c.5752A > C (Thr1918Pro) and c.500_501delTT (Phe167Cysfs*7) in the NBAS gene. CONCLUSIONS: To our best knowledge, these novel mutations in the NBAS gene have not been reported. Normal bone age with growth hormone deficiency in this patient is different from the patients with SOPH syndrome that have been previously reported. These findings enrich the mutant spectrum of the NBAS gene and add our understanding of SOPH syndrome.