Figure
Genetic and phenotypic features of patients with CASP2 variants and literature review of patients with CRADD and PIDD1-associated diagnoses.
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Lissencephaly (LIS) is a malformation of cortical development due to deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. Thirty-one LIS-associated genes have been previously described. Recently, biallelic pathogenic variants in CRADD and PIDD1 , have associated with LIS impacting the previously established role of...
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Context 1
... 26 years old, he has speech delay, behavioral problems with intolerance to frustration, poor social skills, and autistic features. His neurological evaluation showed axial and peripheral hypotonias, and upper motor neuron signs, such as weakness, spasticity, and hyperreflexia (Table 1). ...Context 2
... 5. Family 5, individual II-1 was a 6-year-old from a distantly related Iranian parents who was born at term after an uneventful pregnancy (Fig. 1A). He had history of hypotonia, DD, hydrocephaly and seizures which was started at the age of 4 years old and respond well to medication bilateral optic atrophy as well as mildly abnormal uncoordinated gait (Table 1). ...Context 3
... the c.130 C > T was observed once among 276,302 alleles in a heterozygous state in the deCAF database [24]. Moreover, no other candidate variants were identified in well-known LIS-related genes in the patients' exome data (Table 1S). ...Context 4
... the past few years, biallelic pathogenic variants in CRADD and PIDD1 have been associated with LIS, anterior-predominant pachygyria, and ID (Table 1) [7][8][9][27][28][29][30][31][32]. This finding has drawn attention to the PIDDosome complex, suggesting additional biological functions aside from DNA-damage induced apoptosis. ...Context 5
... patients shared isolated LIS without other congenital anomalies. In addition to LIS, mild to moderate ID, relative or absolute megalencephaly, and seizures were other phenotypic features in the patients (Table 1). The authors proposed that reduced apoptosis is a novel developmental mechanism for cortical malformations [7]. ...Context 6
... researchers suggested that the disease hallmark is frontotemporal predominant pachygyria with mild cortical thickening. In this series, aggressive behavior was found in nearly half of the patients, EEG abnormalities in five patients, and megalencephaly in three patients (Table 1). ...Context 7
... mild and nonspecific dysmorphic features were reported in most patients. Brain MRIs of the patients revealed a spectrum of cerebral cortical anomalies, mainly consistent with anterior-predominant pachygyria (Table 1). The thickness of the cortex was reported to be above the normal limit of 4 mm for most cortical regions in the patients. ...Context 8
... 26 years old, he has speech delay, behavioral problems with intolerance to frustration, poor social skills, and autistic features. His neurological evaluation showed axial and peripheral hypotonias, and upper motor neuron signs, such as weakness, spasticity, and hyperreflexia (Table 1). ...Context 9
... 5. Family 5, individual II-1 was a 6-year-old from a distantly related Iranian parents who was born at term after an uneventful pregnancy (Fig. 1A). He had history of hypotonia, DD, hydrocephaly and seizures which was started at the age of 4 years old and respond well to medication bilateral optic atrophy as well as mildly abnormal uncoordinated gait (Table 1). ...Context 10
... the c.130 C > T was observed once among 276,302 alleles in a heterozygous state in the deCAF database [24]. Moreover, no other candidate variants were identified in well-known LIS-related genes in the patients' exome data (Table 1S). ...Context 11
... the past few years, biallelic pathogenic variants in CRADD and PIDD1 have been associated with LIS, anterior-predominant pachygyria, and ID (Table 1) [7][8][9][27][28][29][30][31][32]. This finding has drawn attention to the PIDDosome complex, suggesting additional biological functions aside from DNA-damage induced apoptosis. ...Context 12
... patients shared isolated LIS without other congenital anomalies. In addition to LIS, mild to moderate ID, relative or absolute megalencephaly, and seizures were other phenotypic features in the patients (Table 1). The authors proposed that reduced apoptosis is a novel developmental mechanism for cortical malformations [7]. ...Context 13
... researchers suggested that the disease hallmark is frontotemporal predominant pachygyria with mild cortical thickening. In this series, aggressive behavior was found in nearly half of the patients, EEG abnormalities in five patients, and megalencephaly in three patients (Table 1). ...Context 14
... mild and nonspecific dysmorphic features were reported in most patients. Brain MRIs of the patients revealed a spectrum of cerebral cortical anomalies, mainly consistent with anterior-predominant pachygyria (Table 1). The thickness of the cortex was reported to be above the normal limit of 4 mm for most cortical regions in the patients. ...Citations
... Lissencephaly is a rare inherited neurological disorder caused by abnormal neuronal migration, resulting in the absence or loss of sulci and gyri, accompanied by abnormal histological structure of the cerebral cortex (23). Affected children present with microcephaly, global developmental delay, early onset of epileptic infantile spasms in infancy, and intellectual disability (24). ...
Tubulin plays an essential role in cortical development, and TUBA1A encodes a major neuronal α-tubulin. Neonatal mutations in TUBA1A are associated with severe brain malformations, and approximately 70% of patients with reported cases of TUBA1A mutations exhibit lissencephaly. We report the case of a 1-year-old boy with the TUBA1A nascent mutation c.1204C >T, p.Arg402Cys, resulting in lissencephaly, developmental delay, and seizures, with a brain MRI showing normal cortical formation in the bilateral frontal lobes, smooth temporo-parieto-occipital gyri and shallow sulcus. This case has not been described in any previous report; thus, the present case provides new insights into the broad disease phenotype and diagnosis associated with TUBA1A mutations. In addition, we have summarized the gene mutation sites, neuroradiological findings, and clinical details of cases previously described in the literature and discussed the differences that exist between individual cases of TUBA1A mutations through a longitudinal comparative analysis of similar cases. The complexity of the disease is revealed, and the importance of confirming the genetic diagnosis from the beginning of the disease is emphasized, which can effectively shorten the diagnostic delay and help clinicians provide genetic and therapeutic counseling.
... Uctepe et al. describe lissencephaly in association with biallelic CASP2 variants. CASP2 interacts with CRADD and PIDD1 as part of the PIDDosome [13]. There are overlapping clinical and neuroimaging features. ...
Caspase-2, a highly conserved member of the caspase family, is considered an initiator caspase that triggers apoptosis in response to some cellular stresses. Previous studies suggest that an intracellular multi-protein complex PIDDosome, induced by genotoxic stress, serves as a platform for caspase-2 activation. However, due to caspase-2's inability to process effector caspases, the mechanism underlying caspase-2-mediated cell death upon PIDDosome activation remains unclear. Here we conducted an unbiased genome-wide genetic screen and identified that the Bcl2 family protein BID is required for PIDDosome-induced, caspase-2-mediated apoptosis. PIDDosome-activated caspase-2 directly and functionally processes BID to signal the mitochondrial pathway for apoptosis induction. Additionally, a designed chemical screen identified a compound, HUHS015, that specifically activates caspase-2-mediated apoptosis. HUHS015-stimulated apoptosis also requires BID but is independent of the PIDDosome. Through extensive structure-activity relationship efforts, we identified a derivative with a potency of ~ 60 nmol/L in activating caspase-2-mediated apoptosis. The HUHS015-series of compounds act as efficient agonists that directly target the interdomain linker in caspase-2, representing a new mode of initiator caspase activation. Human and mouse caspase-2 differ in two crucial residues in the linker, rendering a selectivity of the agonists for human caspase-2. The caspase-2 agonists are valuable tools to explore the physiological roles of caspase-2-mediated cell death and a base for developing small-molecule drugs for relevant diseases.
