Chromosome Rearrangements and Disease

The overall goals of the group are to elucidate the causative genetic defects of human neurodevelopmental disorders (NDD) by using state-of-the art genetics and genomics strategies and to understand the functional relevance of pathogenic variants and the cell protein signaling networks the respective proteins are embedded in. The results will provide insight into normal and disturbed gene functions and into molecular pathways, and they will considerably improve our understanding of the biological and cellular mechanisms underlying normal brain development.

Our group has actively searched for novel NDD genes by systematic mapping of chromosome breakpoints and applying whole exome or whole genome sequencing. Through these activities we have discovered or contributed to the discovery of numerous genes for various forms of NDD (e.g. CDKL5, PQBP1, AUTS2, ARHGEF9, DYRK1A, FOXG1, ZC4H2, CLCN4, CNKSR2, GABRA3, EIF2S3, RLIM, MSL3).

We currently re-investigate those patients and families in which we could not identify the disease-relevant variant in the protein-coding regions of genes or the identified variants in known disease genes have been interpreted as of uncertain clinical significance.

These activities are complemented by in vitro and in vivo studies on previously discovered and newly identified NDD genes and proteins, partly in collaboration with other groups.

CDKL5 is implicated in an X-linked intellectual disability syndrome with early onset epileptic encephalopathy

We have shown that mutations in the X-linked gene CDKL5/STK9 are a significant cause of a neurodevelopmental disorder (CDKL5 deficiency disorder (CDD), previously called atypical Rett syndrome (RTT) or variant of RTT), which affects predominantly girls (Kalscheuer et al, Am J Hum Genet 2003; Tao et al, Am J Hum Genet 2004; Córdova-Fletes et al, Clin Genet 2010; Rademacher et al, Neurogenetics 2011). The main clinical features include early onset epileptic encephalopathy with seizures starting within the first five months of life, severe developmental delay, deceleration of head growth, impaired communication and, often, hand stereotypies.

CDKL5 encodes a serine-threonine kinase. Its N-terminal catalytic domain shares homology with members of the cyclin-dependent kinase (CDK) family and mitogen activated proteins (MAP) kinases. We have established that in primary neurons CDKL5 is localized at excitatory synapses and contributes to correct dendritic spine structure and synapse activity. CDKL5 interacts with the specific Netrin G1 receptor NGL-1, which plays a crucial role in early synapse formation and maturation. CDKL5 phosphorylates NGL-1 on a serine residue close to the cytoplasmic C-terminal PDZ binding domain. This phosphorylation is necessary (i) for reinforcing the interaction between CDKL5 and NGL-1 and (ii) for promoting a stable association between NGL-1 and PSD95, a major protein of the postsynaptic density which plays an important role in synaptic plasticity. Our findings suggested a critical regulatory role for CDKL5 in the formation of excitatory synapses by coupling, through NGL-1 phosphorylation, the Netrin G1-NGL-1 adhesion with the recruitment of PSD95 (Ricciardi et al, Nat Cell Biol 2012).

Current studies include investigating other newly identified CDKL5 interacting proteins and candidate kinase substrates using in vitro and in vivo model systems to answer the fundamental question of how CDKL5 mutations translate into synaptic plasticity and learning and memory deficits.

Deleterious de novo variants of X-linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita (ZC4H2-Associated Rare Disorders, ZARD)

ZC4H2 is one of the more commonly mutated X-linked arthrogryposis multiplex congenita and X-linked intellectual disability genes. It encodes a member of the zinc-finger domain-containing protein family. De novo and inherited pathogenic variants in this gene cause rare syndromic disorders in males and females (previously known as Wieacker-Wolff syndrome) with central and peripheral nervous system involvement. Of note, females with deleterious de novo ZC4H2 variants presented with phenotypes ranging from mild to severe, and their clinical features overlapped with those seen in affected males (Hirata et al, Am J Hum Genet 2013, Frints et al Hum Mut 2019). Current investigations aim at determining the molecular and cellular mechanisms underlying the disorders.

CLCN4 is implicated in X-linked intellectual disability and behavior disorders

Another focus of our current studies is the X-linked gene CLCN4 implicated in syndromic X-linked intellectual disability. The ultimate goal is to better understand the pathophysiology of CLCN4 related disorder a prerequisite for translational research. CLCN4 encodes the chloride/hydrogen ion exchanger ClC-4 prominently expressed in brain. De novo and inherited pathogenic variants in this gene are associated with syndromic intellectual disability and behavior and seizure disorders in males and females (Hu et al, Mol Psychiatry 2016; Palmer et al, Mol Psychiatry 2018). In close collaboration with Dr. E. Palmer and Prof. M. Pusch we are currently investigating the question how we can better discern the pathogenicity of novel missense variants and better understand the effect of heterozygous variants identified in females.

EIF2S3 is implicated in a clinical variable X-linked intellectual disability syndrome

Previous investigations revealed that EIF2S3, which codes for the γ subunit of eukaryotic translation initiation factor 2 (eIF2), causes the X-linked MEHMO (Mental retardation, Epilepsy, Hypogonadism, Microcephaly, Obesity) syndrome. eIF2γ is crucial for initiation of protein synthesis and regulation of the integrated stress response. Interestingly, studies in patient-derived fibroblasts suggested increased integrated stress response activation due to the frameshift mutation identified in the families. Functional assays performed in yeast by the group of Prof. T. Dever demonstrated that the variants identified in the families impaired eIF2γ function and thereby supported pathogenicity. Our results added MEHMO syndrome to a group of disorders that are associated with eIF2, causing dysregulation of translation (Skopkova, Hennig, et al, Hum Mut 2017). Ongoing studies, in close collaboration with the group of Prof. T. Dever, address the potential impact of EIF2S3 variants on eIF2γ function.

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