A prenatal case of lissencephaly with cerebellar hypoplasia: New mutation in RELN gene.
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ABSTRACT:
SUBMITTER: Balza C
PROVIDER: S-EPMC8645177 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Lissencephaly is an inherited developmental disorder in which neuronal migration is impaired. A type of lissencephaly associated with cerebellar hypoplasia (LCH) was diagnosed in a commercial flock of Spanish Churra sheep. The genotyping of 7 affected animals and 33 controls with the OvineSNP50 BeadChip enabled the localization of the causative mutation for ovine LCH to a 4.8-Mb interval on sheep chromosome 4 using genome-wide association and homozygosity mapping. The RELN gene, which is located within this interval, was considered a strong positional and functional candidate because it plays critical roles in neuronal migration and layer formation. By performing a sequencing analysis of this gene's specific mRNA in a control lamb, we obtained the complete CDS of the ovine RELN gene. The cDNA sequence from an LCH-affected lamb revealed a deletion of 31 bp (c.5410_5440del) in predicted exon 36 of RELN, resulting in a premature termination codon. A functional analysis of this mutation revealed decreased levels of RELN mRNA and a lack of reelin protein in the brain cortex and blood of affected lambs. This mutation showed a complete concordance with the Mendelian recessive pattern of inheritance observed for the disease. The identification of the causal mutation of LCH in Churra sheep will facilitate the implementation of gene-assisted selection to detect heterozygous mutants, which will help breeders avoid at-risk matings in their flocks. Moreover, the identification of this naturally occurring RELN mutation provides an opportunity to use Churra sheep as a genetically characterized large animal model for the study of reelin functions in the developing and mature brain.
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Project description:ObjectiveWe aimed to identify pathogenic variants in a girl with epilepsy, developmental delay, cerebellar ataxia, oral motor difficulty, and structural brain abnormalities with the use of whole-exome sequencing.MethodsWhole-exome trio analysis and molecular functional studies were performed in addition to the clinical findings and neuroimaging studies.ResultsBrain MRI showed mild pachygyria, hypoplasia of the cerebellar vermis, and abnormal foliation of the cerebellar vermis, suspected for a variant in one of the genes of the Reelin pathway. Trio whole-exome sequencing and additional functional studies were performed to identify the pathogenic variants. Trio whole-exome sequencing revealed compound heterozygous splice variants in DAB1, both affecting the highly conserved functional phosphotyrosine-binding domain. Expression studies in patient-derived cells showed loss of normal transcripts, confirming pathogenicity.ConclusionsWe conclude that these variants are very likely causally related to the cerebral phenotype and propose to consider loss-of-function DAB1 variants in patients with RELN-like cortical malformations.
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Project description:The positive regulatory (PR) domain containing 13 (PRDM13) putative chromatin modifier and transcriptional regulator functions downstream of the transcription factor PTF1A, which controls GABAergic fate in the spinal cord and neurogenesis in the hypothalamus. Here, we report a recessive syndrome associated with PRDM13 mutation. Patients exhibited intellectual disability, ataxia with cerebellar hypoplasia, scoliosis, and delayed puberty with congenital hypogonadotropic hypogonadism (CHH). Expression studies revealed Prdm13/PRDM13 transcripts in the developing hypothalamus and cerebellum in mouse and human. An analysis of hypothalamus and cerebellum development in mice homozygous for a Prdm13 mutant allele revealed a significant reduction in the number of Kisspeptin (Kiss1) neurons in the hypothalamus and PAX2+ progenitors emerging from the cerebellar ventricular zone. The latter was accompanied by ectopic expression of the glutamatergic lineage marker TLX3. Prdm13-deficient mice displayed cerebellar hypoplasia and normal gonadal structure, but delayed pubertal onset. Together, these findings identify PRDM13 as a critical regulator of GABAergic cell fate in the cerebellum and of hypothalamic kisspeptin neuron development, providing a mechanistic explanation for the cooccurrence of CHH and cerebellar hypoplasia in this syndrome. To our knowledge, this is the first evidence linking disrupted PRDM13-mediated regulation of Kiss1 neurons to CHH in humans.
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Project description:BackgroundLissencephaly (LIS) is a malformation of cortical development with broad gyri, shallow sulci and thickened cortex characterized by developmental delays and seizures. Currently, 20 genes have been implicated in LIS. However, GRP56-related LIS has never been reported. GRP56 is considered one of the causative genes for bilateral frontoparietal polymicrogyria. Here, we report a twin infant with LIS and review the relevant literature. The twins both carried the novel compound heterozygous GPR56 mutations.Case summaryA 5-mo-old female infant was hospitalized due to repeated convulsions for 1 d. The patient had a flat head deformity that manifested as developmental delays and a sudden onset of generalized tonic-clonic seizures at 5 mo without any causes. The electroencephalography was normal. Brain magnetic resonance imaging revealed a simple brain structure with widened and thickened gyri and shallow sulci. The white matter of the brain was significantly reduced. Patchy long T1 and T2 signals could be seen around the ventricles, which were expanded, and the extracerebral space was widened. Genetic testing confirmed that the patient carried the GPR56 gene compound heterozygous mutations c.228delC (p.F76fs) and c.1820_1821delAT (p.H607fs). The unaffected father carried a heterozygous c.1820_1821delAT mutation, and the unaffected mother carried a heterozygous c.228delC mutation. The twin sister carried the same mutations as the proband. The patient was diagnosed with LIS.ConclusionThis is the first case report of LIS that is likely caused by mutations of the GPR56 gene.
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