鋅指转录因子ZIC3在内脏异位中的研究现状及进展

内脏异位是由于左右非对称性发育异常所致,常与胸腹腔器官的异常偏侧化有关。心脏经常受累,且心脏受累的严重程度通常决定其预后效果。内脏异位患者有特征性的心血管畸形、内脏器官的异常排列以及中线结构发育畸形。在内脏异位患者中第一个被发现有突变的基因是编码锌指转录因子的ZIC3。很多研究证实,ZIC3突变可导致X连锁内脏异位,而且在孤立性先心病中也发现了ZIC3的突变。至今,在内脏异位患者中发现有13个ZIC3突变,其中包括无义突变、错义突变、沉默突变、移码突变以及易位突变等。然而,ZIC3基因在内脏异位,特别是伴复杂先心病中的致病机理仍不是很清楚。本文就ZIC3结构、作用、突变以及其在内脏异位伴先心病中的研究现状及存在的问题做一综述。     

Novel noncanonical splice site variant causes mild CHD7-related disorder with variable intrafamilial expressivity

The clinical diagnosis criteria for CHARGE syndrome have been revised several times in the last 25 years. Variable expressivity and reduced penetrance are known, particularly in mild and familial cases. Therefore, it has been proposed to include the detection of a pathogenic CHD7 variant as a major diagnostic criterion. However, intronic variants not located at the canonical splice site are still underrepresented in mutation databases, often because functional analysis is not performed in the diagnostic setting. Here, we report a two-generation family that did not meet the criteria for CHARGE syndrome, until the molecular findings were taken into account. By exome sequencing, we detected an intronic variant in a male individual, who presented with unilateral external ear malformation, bilateral semicircular canal aplasia, polydactyly, vertebral body fusion and a heart defect. The variant was inherited by his mother, who also had bilateral semicircular canal aplasia additionally to unilateral sensorineural hearing impairment, unilateral mandibular palpebral synkinesia, orofacial cleft, and dysphagia. Using RNA studies, we were able to demonstrate that aberrant splicing occurs at an upstream cryptic splice acceptor site, resulting in a frameshift and premature stop of translation. Our data show causality of the noncanonical intronic CHD7 variant and end the diagnostic odyssey of this unsolved phenotype of the family.     

Inherited variants in CHD3 show variable expressivity in Snijders Blok-Campeau syndrome

PurposeCommon diagnostic next-generation sequencing strategies are not optimized to identify inherited variants in genes associated with dominant neurodevelopmental disorders as causal when the transmitting parent is clinically unaffected, leaving a significant number of cases with neurodevelopmental disorders undiagnosed.MethodsWe characterized 21 families with inherited heterozygous missense or protein-truncating variants in CHD3, a gene in which de novo variants cause Snijders Blok-Campeau syndrome.ResultsComputational facial and Human Phenotype Ontology–based comparisons showed that the phenotype of probands with inherited CHD3 variants overlaps with the phenotype previously associated with de novo CHD3 variants, whereas heterozygote parents are mildly or not affected, suggesting variable expressivity. In addition, similarly reduced expression levels of CHD3 protein in cells of an affected proband and of healthy family members with a CHD3 protein-truncating variant suggested that compensation of expression from the wild-type allele is unlikely to be an underlying mechanism. Notably, most inherited CHD3 variants were maternally transmitted.ConclusionOur results point to a significant role of inherited variation in Snijders Blok-Campeau syndrome, a finding that is critical for correct variant interpretation and genetic counseling and warrants further investigation toward understanding the broader contributions of such variation to the landscape of human disease.     

Progressive diaphyseal dysplasia: A three-generation family with markedly variable expressivity

Progressive diaphyseal dysplasia was found in a 3-generation family including 18 affected individuals. We describe the clinical and radiographic manifestations in 6 of 18 patients with this autosomal-dominant bone dysplasia and the good symptomatic response to corticosteroid treatment in one of these. The variability of manifestations of the disease in this family and in others previously described seems to depend on the sex of the patient and the parental origin of the mutation. The patients with more severe symptoms are males who inherited an allele of paternal origin. We suggest that the progressive diaphyseal dysplasia gene has a function in endochondral bone formation and that its mutation is a dynamic one with repeat expansion enhanced in father-to-son transmission. Am. J. Med. Genet. 71:348–352, 1997. © 1997 Wiley-Liss, Inc.     

Two-hit wonder: a novel genetic model to explain variable expressivity in severe pediatric phenotypes

A recurrent 16p12.1 microdeletion supports a two‐hit model for severe developmental delay Girirajan et al. (2010) Nature Genetics 42(3):203–209     

Novel LAMB3 mutations cause non‐syndromic amelogenesis imperfecta with variable expressivity

The field of genetics is evolving rapidly, significantly expanding the number of clinically useful genetic tests. The cost of genetic testing has created an increasing burden on public health care budgets. In Canada, funding bodies have responded by developing independent systems. Key individuals in each province and territory participated in a semi‐structured interview regarding the process in their jurisdiction to approve funding for referred out genetic testing and their decision‐making criteria. Two themes were identified: the importance of clinical utility in decision‐making and the utilization of genetic specialists as gate keepers. Allocation of a specific budget appears to be associated with some fiscal responsibility. Collaboration between provincial and territorial bodies may lead to a more unified approach across Canada.     

iPS cells to model CDKL5-related disorders

Rett syndrome (RTT) is a progressive neurologic disorder representing one of the most common causes of mental retardation in females. To date mutations in three genes have been associated with this condition. Classic RTT is caused by mutations in the MECP2 gene, whereas variants can be due to mutations in either MECP2 or FOXG1 or CDKL5. Mutations in CDKL5 have been identified both in females with the early onset seizure variant of RTT and in males with X-linked epileptic encephalopathy. CDKL5 is a kinase protein highly expressed in neurons, but its exact function inside the cell is unknown. To address this issue we established a human cellular model for CDKL5-related disease using the recently developed technology of induced pluripotent stem cells (iPSCs). iPSCs can be expanded indefinitely and differentiated in vitro into many different cell types, including neurons. These features make them the ideal tool to study disease mechanisms directly on the primarily affected neuronal cells. We derived iPSCs from fibroblasts of one female with p.Q347X and one male with p.T288I mutation, affected by early onset seizure variant and X-linked epileptic encephalopathy, respectively. We demonstrated that female CDKL5-mutated iPSCs maintain X-chromosome inactivation and clones express either the mutant CDKL5 allele or the wild-type allele that serve as an ideal experimental control. Array CGH indicates normal isogenic molecular karyotypes without detection of de novo CNVs in the CDKL5-mutated iPSCs. Furthermore, the iPS cells can be differentiated into neurons and are thus suitable to model disease pathogenesis in vitro.     

Familial ectrodactyly and polydactyly: variable expressivity of one single gene - embryological considerations

Coexistence of polydactyly and ectrodactyly in a sibship of four children is reported. One boy and one male twin presented polydactyly, the male monozygotic cotwin had a lobster claw deformity of the right foot and the last child, a girl, had absence of the phalanges of the right hand. Embryological explanation of these apparently totally opposed malformations is attempted.     

Branchio-oto-renal syndrome: reduced penetrance and variable expressivity in four generations of a large kindred

The family on which this report is based is of interest because it contains individuals with the branchio-oto-renal (BOR) syndrome who have renal hypoplasia or malformations of the kidney or collecting system including duplication; only branchial and ear anomalies; and apparent nonpenetrance of the syndrome. This report provides evidence to support the hypothesis that in some families variable expressivity includes duplication of the urinary collecting system in individuals with other manifestations of the BOR syndrome as well as individuals with branchial and ear anomalies who have apparently normal kidneys.     

MAGEL2-related disorders: A study and case series

Pathogenic MAGEL2 variants result in the phenotypes of Chitayat-Hall syndrome (CHS), Schaaf-Yang syndrome (SYS) and Prader-Willi syndrome (PWS). We present five patients with mutations in MAGEL2, including the first patient reported with a missense variant, adding to the limited literature. Further, we performed a systematic review of the CHS and SYS literature, assess the overlap between CHS, SYS and PWS, and analyze genotype-phenotype correlations among them. We conclude that there is neither a clinical nor etiological difference between CHS and SYS, and propose that the two syndromes simply be referred to as MAGEL2-related disorders.     

A novel mutation in the EIF2AK3 gene with variable expressivity in two patients with Wolcott-Rallison syndrome

Mutations in the EIF2AK3 gene have been identified in patients with Wolcott-Rallison syndrome - a rare autosomal recessive disorder associated with permanent neonatal insulin-dependent diabetes. Despite the fact that different mutations have been observed in every single unrelated case reported so far, most patients presented with similar characteristics, such as osteopenia, epiphyseal dysplasia as well as hepatic and/or renal dysfunction. The EIF2AK3 gene was analyzed using a PCR-based sequencing approach in two Wolcott-Rallison patients and their parents. We report two cases from different families carrying the same and novel truncating nonsense mutation in the EIF2AK3 gene that encodes the pancreatic eukaryotic initiation factor 2alpha kinase 3. This mutation clearly displays different clinical characteristics in the two patients we examined. Remarkably, the onset of diabetes was different for the two patients, and there was also heterogeneity in other clinical manifestations. These cases illustrate the important role of alternative pathways that could, to some extent, take over or supplement a defective metabolic pathway. This supports the idea that there is no simple relationship among clinical manifestations and EIF2AK3 mutations.     

Dandy-Walker malformation associated with heterozygous ZIC1 and ZIC4 deletion: Report of a new patient

We report on a female patient with Dandy-Walker malformation possibly caused by heterozygous loss of ZIC1 and ZIC4. The patient presented with mental retardation, epilepsy, and multiple congenital malformations including spina bifida, mild dysmorphic facial features including, thick eyebrows, broad nose, full lips, macroglossia, and hypoplasia of the cerebellar vermis with enlargement of the fourth ventricle on brain magnetic resonance imaging, which is consistent with Dandy-Walker malformation. A chromosome analysis showed interstitial deletion of chromosome 3q23-q25.1. Fluorescence in situ hybridization (FISH) and microarray-based genomic analysis revealed the heterozygous deletion of ZIC1 and ZIC4 loci on 3q24. Her facial features were not consistent with those observed in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) involving FOXL2 abnormality. Other deleted genes at 3q23-25.1 might contribute to the dysmorphic facial appearance. A milder phenotype as the Dandy-Walker malformation in our patient supports the idea that modifying loci/genes can influence the development of cerebellar malformation.     

The Wiedemann-Beckwith syndrome: pedigree studies on five families with evidence for autosomal dominant inheritance with variable expressivity

We describe 18 individuals from five unrelated families with various manifestations of the Wiedemann-Beckwith syndrome. Pedigree analysis was performed on the 5 families and on another 19 families in the literature, each of which included more than one affected person. The following findings were obtained: 1) the clinical manifestations among the affected individuals were highly variable--those obvious in infancy tended to become less distinct with increasing age; 2) the syndrome was transmitted directly and vertically through three generations in four families, and through two generations in seven families; 3) male-to-male transmission was noted once; 4) the sex ratio in the affected individuals was not significantly different from 1; 5) the segregation ratio of the trait among the sibs of the probands was 0.571 +/- 0.066; 6) the affected + carrier/normal ratio was one among the offspring of the affected individuals and obligate carriers; 7) phenotrance (the expected presence of the trait in a generation) of the syndrome in the sibship of probands was complete, whereas that in earlier generations appeared low. The discrepancy is attributable to the lessening of the clinical features with increasing age as well as to a possibly less aggressive search for abnormalities in older generations. These findings indicate that the syndrome is an autosomal dominant trait with variable expressivity. High-resolution chromosome banding analysis in seven affected individuals and their respective parents showed no abnormalities.     

Ubiquitin biology in neurodegenerative disorders: From impairment to therapeutic strategies

The abnormal accumulation of neurotoxic proteins is the typical hallmark of various age-related neurodegenerative disorders (NDDs), including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis and Multiple sclerosis. The anomalous proteins, such as Aβ, Tau in Alzheimer’s disease and α-synuclein in Parkinson’s disease, perturb the neuronal physiology and cellular homeostasis in the brain thereby affecting the millions of human lives across the globe. Here, ubiquitin proteasome system (UPS) plays a decisive role in clearing the toxic metabolites in cells, where any aberrancy is widely reported to exaggerate the neurodegenerative pathologies. In spite of well-advancement in the ubiquitination research, their molecular markers and mechanisms for target-specific protein ubiquitination and clearance remained elusive. Therefore, this review substantiates the role of UPS in the brain signaling and neuronal physiology with their mechanistic role in the NDD’s specific pathogenic protein clearance. Moreover, current and future promising therapies are discussed to target UPS-mediated neurodegeneration for better public health.     

CAPN1 mutations: Expanding the CAPN1-related phenotype: From hereditary spastic paraparesis to spastic ataxia

Aims and objectiveTo characterize the phenotype of CAPN1 (SPG76) mutations in patients diagnosed with hereditary spastic paraplegia (HSP).BackgroundThe CAPN1 gene, located on chromosome 11q13.1, is a protein-coding gene involved in neuronal plasticity, migration, microtubular regulation and cerebellar development. Several families with CAPN1 mutations have recently been reported to present with autosomal recessive (AR) HSP and/or ataxia.MethodPatients with HSP were identified through neurological and genetic clinics with detailed phenotyping. Whole exome sequencing revealed novel pathogenic CAPN1 mutations in four patients from 3 families.ResultsAffected families were of Turkish, Japanese, and Punjabi descent and all were consanguineous. Onset of spastic paraplegia in the four patients was between 20 and 37 years. Two also had mild ataxia. Three different novel, homozygous mutations in CAPN1 were found: c.2118+1G > T, c.397C > T, c.843+1G > C. The patient with the earliest onset also manifested profound muscle weakness, likely related to a second homozygous mutation in DYSF (dysferlinopathy).ConclusionsThe phenotype of AR CAPN1 mutations appears to be spastic paraplegia with or without ataxia; onset is most commonly in adulthood. Eye movement abnormalities, skeletal defects, peripheral neuropathy and amyotrophy can sometimes be seen. Occasionally, patients can present with ataxia, illustrating the genotypic and phenotypic overlap between HSP and spastic ataxia. With the advent of exome sequencing, mutations in more than one gene can be identified, which may contribute to the phenotypic variation, even within a family.