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Sidst opdateret: 2/12 2020
Lisbeth Birk Møller

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Lisbeth Birk Møller

Seniorforsker, biokemiker, cand.scient., ph.d.


Medicinsk genetisk laboratorium
Center for Anvendt Human Molekylærgenetik


Kennedy Centret
Gl. Landevej 7

2600 Glostrup


Tlf.: 29204830

Fax.: 43431130



Foto af Lisbeth Birk Møller

Curriculum vitae and Publications 

Functional Genomics; Mutation identification; Locus/gene identification; X-inactivation;  Gene Expression; Real-time PCR; mRNA Splicing; In vitro translation; functional investigations; Cell culturing; Fibroblasts reprogramming; iPSC; RPE generation; Protein localization (Western blotting, Immunofluorescence); Copper dependent cellular localization; Primary cilium; Cell signaling (mTOR, Hedgehog, Autophagy; TGFbeta); Treatment; Pain models; Menkes disease; Wilson disease; PKU; Dopa-responsive dystonia; Retinal dystrophy; Bardet Biedl disease; Usher syndrome; Pain; Tuberous sclerosis; Parkinsonism.

Main research
The major part of my research has been based on molecular findings in patients with rare diseases. We have investigated genotype/phenotype correlations, concentrated on the molecular effect of mutations at all levels.  I am interested in the effects at the cellular level but also in animal models and selected group of patients. The main aim of my research is development of new treatment strategies.
At the cellular level we have investigated the effect of mutations on gene expression, X-inactivation, mRNA splicing, read-through of premature stop codons, re-initiation of translation, cellular localization and function of the resulting protein product with regard to copper dependent trafficking, and effect on basic signalling pathways coordinated by the primary cilium (mTOR, Hedgehog, Autophagy; TGFbeta). We are working on generation of patient specific iPSC as a source for disease models, with focus on retinal dystrophy. Recently we have reprogrammed iPSC into RPE cells.
At the organism level we have investigated the potential effect of copper treatment of animal models for Menkes disease. Treatment of PKU patients, and/or mice model, with large neutral amino acids or Phe free diet. Investigation of the effect of BH4, on pain perception in mice models, and in patients with GCH1 mutations.

Ongoing research

Reduced concentration of tetrahydrobiopterin does not affect the pain sensitivity in Dopa-Responsive Dystonia patients with GTP Cyclohydrolase 1 mutations
Human studies have indicated a correlation between polymorphisms “the pain protective” (PP) haplotype in the GCH1 gene, with slightly reduced activity of GCH1, and reduced pain after low back pain surgery or capsaicin provoked pain hypersensitivity. Genetic defects in GCH1 are responsible for the rare dominant disorder “dopa-responsive dystonia” (DRD). In the present study, we investigate GCH1 associated biomarkers and pain sensitivity in a cohort of 22 DRD patients and 36 controls “Full-cohort”, and in a family specific subcohort “Fam-subcohort”, which is assumed to be more homogenous with respect to within-group properties than unrelated persons. In this family, the DRD patients were heterozygous for the PP haplotype in cis with the GCH1 disease causing mutation c.899T>C. The DRD patients were found to have statistically significant reduced urine and/or blood levels of BH4, NP and BP and reduced amount of GCH1 protein in cytokine stimulated fibroblast-cultures compared with the controls. However, no statistical significant differences in pain sensitivity between DRD patients and controls, neither in the “Full-cohort” nor in the “Fam-subcohort” was observed. In contrast, gender and age affect specific pain responses. In conclusion, GCH1 mutations resulting in profound reduction in BH4 level are not associated with reduced pain sensitivity.
Tumor suppressor proteins TSC1 and TSC2 regulate Hedgehog signaling and length of primary cilia via diverse pathways involving TGFß, mTOR and Wnt signaling (PhD project)
Primary cilia which extend from the surface of most quiescent cell types are sensory organelles known to play a critical role in the coordination of multiple cellular signaling pathways, including Hedgehog (HH), Wingless/Int (Wnt) and more recently TGFß and mTOR signaling. The heterodimeric complex TSC, formed by TSC1 and TSC2 is well known as a negative regulator of protein synthesis by inactivation mTOR complex 1 (mTORC1) at energy limiting states. In contrast, not much is known according to mTOR and the interplay between the other signaling pathways including the distinct functions of TSC1 and TSC2. In the ongoing study we found that both TSC1-/- and TSC2-/- mouse embryonic fibroblasts display impaired HH signaling, but via two different mechanisms. While the interaction between TSC2 and HH signaling was regulated by mTORC1, the interaction between TSC1 and HH signaling was coordinated by the TGF-ß-SMAD2/3 signaling pathway. Impaired TGFb signaling inhibits the expression of Gli2, and subsequently Wnt5a expression, involved in cilia disassembly, resulting in a long cilia phenotype in TSC1-/- cells. In contrast TSC2-/- cells exhibited a short cilia phenotype. These results provide new information about the distinct functions TSC1 and TSC2 have in regulation of the various signaling pathways that influence Hedgehog signaling. We are still working on the effect of TSC2 in Hedgehog signaling.
Functional investigation of variants identified in patients with retinal dystrophy (Ph.D., Velux project)
By screening 456 patients with retinal dystrophy for mutations in a panel of 124 genes known to be associated with retinal dystrophy, we have been able to identify disease causing mutations in a large fraction of the patients. However, we have also identified a number of variants of uncertain clinical significance (VUS), variants which might or might not be disease causing. Furthermore in more than 100 patients we found more than one possible explanation for the eye symptoms or identified mutations in patients with very atypical phenotype. Functional studies are therefore necessary to obtain final molecular genetic diagnosis. The aim of this PhD project is to investigate the molecular effect of these DNA sequence variants. A large fraction of the genes encode proteins important for the function or structure of the primary cilium (e.g. ARL6, BBIP1, BBS1, BBS2, BBS4, BBS5, BBS7, BBS9, BBS10, BBS12, CEP290, RPGRIP, MKS1, and ALMS1). Clarification of the pathogenesis of variants identified in those might be possible by investigation of the structure (length, number) of the cilia and cilia coordinated pathways e.g. Hedgehog (Hh) in fibroblast obtained from the patients.  In order to clarify the pathogenesis of variants identified in genes important for the function/survival of the photoreceptors, we will work on generation of patient-specific or/and of mutation-specific photoreceptors using the CRISPR/Cas9 system with focus on Bardet-Biedl syndrome. Some variants are in genes important for the function of RPE cells (e.g. MERTK, MYO7A, RPE65, and BEST1). In order to investigate those patient-derived RPE cells needs to be generated and/or the VUS needs to be introduced into a control RPE cell line.

Investigation of the Danish founder mutation c.93C>A (p.Cys31STOP) in MYO7A as a potential target for translational read-through.

Usher syndrome (USH) is the most prevalent genetic cause of combined hearing and vision loss. It is clinically heterogeneous and can be divided into three clinical subtypes, referred as USH1, USH2 and USH3. USH1 is the most severe type, characterized by profound congenital hearing loss, congenital vestibular dysfunction and adjoining blindness, often in the first decade. USH1 accounts for 25%-44% of all USH cases in Europe. Thanks to the ingenious development of cochlear implant, USH patients today have the opportunity to “hear”, but there is so far no treatment to avoid blindness. In our (Kennedy Centers øjenklinik) combined cohort of 100 Danish families with molecular diagnosis of USH, 32 families have USH1, and in 75% of these families, the affected gene was MYO7A. Furthermore one single mutation c.93C>A, leading to p.Cys31STOP accounted for 45% of all MYO7A mutations. The mutation p.Cys31STOP seems to be a Danish founder mutation. The mutation p.Cys31STOP leads to an in frame premature termination after only 31 amino acids. MYO7A is expressed in the hair cells in the cochlea, in the photoreceptor cells, and in the RPE cells. By incubation with aminoglycoside antibiotics like gentamycin G418, it has been shown that the efficiency of the premature in frame STOP codons is reduced, whereas the normal STOP codon is not affected. These antibiotics, promote read-through, cheating the proofreading mechanism, by binding to the ribosomal RNA, and insert of an amino acid at the position for the STOP codon rescuing the production of full-length protein. The purpose of this project is to investigate the Danish founder mutation c.93C>A changing the triplets UGC for cysteine to the STOP codon UGA (p.Cys31Stop) in MYO7A as a potential target for read-through. We want to investigate this effect in patient specific iPSC derived retinal cells.

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