| 1. |
- Kariminejad, Ariana, et al.
(författare)
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Homozygous Null TBX4 Mutations Lead to Posterior Amelia with Pelvic and Pulmonary Hypoplasia
- 2019
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Ingår i: American Journal of Human Genetics. - : Elsevier. - 0002-9297 .- 1537-6605. ; 105:6, s. 1294-1301
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Tidskriftsartikel (refereegranskat)abstract
- The development of hindlimbs in tetrapod species relies specifically on the transcription factor TBX4. In humans, heterozygous loss-of-function TBX4 mutations cause dominant small patella syndrome (SPS) due to haploinsufficiency. Here, we characterize a striking clinical entity in four fetuses with complete posterior amelia with pelvis and pulmonary hypoplasia (PAPPA). Through exome sequencing, we find that PAPPA syndrome is caused by homozygous TBX4 inactivating mutations during embryogenesis in humans. In two consanguineous couples, we uncover distinct germline TBX4 coding mutations, p.Tyr113∗ and p.Tyr127Asn, that segregated with SPS in heterozygous parents and with posterior amelia with pelvis and pulmonary hypoplasia syndrome (PAPPAS) in one available homozygous fetus. A complete absence of TBX4 transcripts in this proband with biallelic p.Tyr113∗ stop-gain mutations revealed nonsense-mediated decay of the endogenous mRNA. CRISPR/Cas9-mediated TBX4 deletion in Xenopus embryos confirmed its restricted role during leg development. We conclude that SPS and PAPPAS are allelic diseases of TBX4 deficiency and that TBX4 is an essential transcription factor for organogenesis of the lungs, pelvis, and hindlimbs in humans.
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| 2. |
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| 3. |
- Haaf, Ezra, 1985, et al.
(författare)
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Data-Driven Estimation of Groundwater Level Time-Series at Unmonitored Sites Using Comparative Regional Analysis
- 2023
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Ingår i: Water Resources Research. - 0043-1397 .- 1944-7973. ; 59:7
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Tidskriftsartikel (refereegranskat)abstract
- A new method is presented to efficiently estimate daily groundwater level time series at unmonitored sites by linking groundwater dynamics to local hydrogeological system controls. The proposed approach is based on the concept of comparative regional analysis, an approach widely used in surface water hydrology, but uncommon in hydrogeology. Using physiographic and climatic site descriptors, the method utilizes regression analysis to estimate cumulative frequency distributions of groundwater levels (groundwater head duration curves, HDC) at unmonitored locations. The HDC is then used to construct a groundwater hydrograph using time series from distance-weighted neighboring monitored (donor) locations. For estimating times series at unmonitored sites, in essence, spatio-temporal interpolation, stepwise multiple linear regression (MLR), extreme gradient boosting (XGB), and nearest neighbors are compared. The methods were applied to 10-year daily groundwater level time series at 157 sites in unconfined alluvial aquifers in Southern Germany. Models of HDCs were physically plausible and showed that physiographic and climatic controls on groundwater level fluctuations are nonlinear and dynamic, varying in significance from “wet” to “dry” aquifer conditions. XGB yielded a significantly higher predictive skill than nearest neighbor and MLR. However, donor site selection is of key importance. The study presents a novel approach for regionalization and infilling of groundwater level time series that also aids conceptual understanding of controls on groundwater dynamics, both central tasks for water resources managers.
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| 4. |
- Haaf, Ezra, 1985, et al.
(författare)
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Data-driven Estimation of Groundwater Level Time-Series Using Comparative Regional Analysis
- 2022
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- A new method is presented to efficiently estimate daily groundwater level time series at unmonitored sites by linking groundwater dynamics to local hydrogeological system controls. The presented approach is based on the concept of comparative regional analysis, an approach widely used in surface water hydrology, but uncommon in hydrogeology. The method uses regression analysis to estimate cumulative frequency distributions of groundwater levels (groundwater head duration curves (HDC)) at unmonitored locations using physiographic and climatic site descriptors. The HDC is then used to construct a groundwater hydrograph using time series from distance-weighted neighboring monitored (donor) locations. For estimating times series at unmonitored sites, in essence, spatio-temporal interpolation, stepwise multiple linear regression, extreme gradient boosting, and nearest neighbors are compared. The methods were applied to ten-year daily groundwater level time series at 157 sites in alluvial unconfined aquifers in Southern Germany. Models of HDCs were physically plausible and showed that physiographic and climatic controls on groundwater level fluctuations are nonlinear and dynamic, varying in significance from “wet” to “dry” aquifer conditions. Extreme gradient boosting yielded a significantly higher predictive skill than nearest neighbor and multiple linear regression. However, donor site selection is of key importance. The study presents a novel approach for regionalization and infilling of groundwater level time series that also aids conceptual understanding of controls on groundwater dynamics, both central tasks for water resources managers.
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| 5. |
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| 6. |
- Tranebjærg, Lisbeth, et al.
(författare)
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The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management
- 2018
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Ingår i: Human Genetics. - : Springer. - 0340-6717 .- 1432-1203. ; 137:2, s. 111-127
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Tidskriftsartikel (refereegranskat)abstract
- Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing impairment (CAPOS) is a rare clinically distinct syndrome caused by a single dominant missense mutation, c.2452G>A, p.Glu818Lys, in ATP1A3, encoding the neuron-specific alpha subunit of the Na+/K+-ATPase α3. Allelic mutations cause the neurological diseases rapid dystonia Parkinsonism and alternating hemiplegia of childhood, disorders which do not encompass hearing or visual impairment. We present detailed clinical phenotypic information in 18 genetically confirmed patients from 11 families (10 previously unreported) from Denmark, Sweden, UK and Germany indicating a specific type of hearing impairment-auditory neuropathy (AN). All patients were clinically suspected of CAPOS and had hearing problems. In this retrospective analysis of audiological data, we show for the first time that cochlear outer hair cell activity was preserved as shown by the presence of otoacoustic emissions and cochlear microphonic potentials, but the auditory brainstem responses were grossly abnormal, likely reflecting neural dyssynchrony. Poor speech perception was observed, especially in noise, which was beyond the hearing level obtained in the pure tone audiograms in several of the patients presented here. Molecular modelling and in vitro electrophysiological studies of the specific CAPOS mutation were performed. Heterologous expression studies of α3 with the p.Glu818Lys mutation affects sodium binding to, and release from, the sodium-specific site in the pump, the third ion-binding site. Molecular dynamics simulations confirm that the structure of the C-terminal region is affected. In conclusion, we demonstrate for the first time evidence for auditory neuropathy in CAPOS syndrome, which may reflect impaired propagation of electrical impulses along the spiral ganglion neurons. This has implications for diagnosis and patient management. Auditory neuropathy is difficult to treat with conventional hearing aids, but preliminary improvement in speech perception in some patients suggests that cochlear implantation may be effective in CAPOS patients.
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