Functional Genetics

We are interested in the identification and characterization of hereditary disorders. A major focus of the group is neurogenetics and ion transport. Our functional studies include the generation and characterization of transgenic- and knockout-mice. 





Genetics and Function of Ion transport



Ion transport is crucial for ionic homeostasis, regulation of the cell volume, transepithelial transport of salt and water, as well as signal transduction. The essential role of the molecules involved in these processes is reflected by a large number of hereditary disorders due to mutations in genes encoding ion channels or -transporters. Over the past years our group has established and analyzed several knockout-mouse models of ion channels/ -transporters to better understand their pathophysiological role in disease.


Selected Publications:


Hübner C.A., Stein V., Hermans-Borgmeyer I., Meyer T., Ballanyi K., Jentsch T.J. (2001) Disruption of KCC2 reveals an essential role of K-Cl-cotransport already in early synaptic inhibition. Neuron 30, 515-24

Boettger T.*, Hübner C.A.*, Maier H., Rust M., Beck F.X., Jentsch T.J. (2002). Deafness and renal tubular acidosis in mice lacking the K-Cl co-transporter KCC4. Nature 416, 874-7 *equally contributing

Hübner C.A., Jentsch T.J. (2002) Ion channels and diseases. Hum Mol Genet, 11, 2435-45

Boettger T., Rust M.B., Maier H., Seidenbecher T., Schweizer M., Keating D.J., Faulhaber J., Ehmke H., Pfeffer C., Scheel O., Lemcke B., Horst J., Leuwer R., Pape H.C., Völkl H., Hübner C.A., Jentsch T.J. (2003) Loss of K-Cl co-transporter KCC3 causes deafness, neurodegeneration and reduced seizure threshold. EMBO Journal 22, 5422-34

Jentsch, T.J., Hübner, C.A., Fuhrmann, J.C. (2004) Ion channels: function unraveled by dysfunction. Nat Cell Biol, 6, 1039-47

Hentschke M., Wiemann M., Hentschke S., Kurth I., Seidenbecher T., Hermans-Borgmeyer I., Jentsch T.J., Gal A., Hübner C.A. (2006) Mice with a targeted disruption of the Cl-/HCO3- exchanger AE3 display a reduced seizure threshold. Mol Cell Biol 26, 182- 91

Tyzio R., Cossart R., Khalilov I., Minlebaev M., Hübner C.A., Represa A., Ben-Ari Y., Khazipov R. Maternal oxytocin triggers a transient inhibitory switch in GABA signaling in the fetal brain during delivery. Science, 314:1788-92, 2006

Rust M.B., Alper S.L., Rudhard Y., Brugnara C., Trudel M., Jentsch T.J., Hübner C.A. Disruption of erythroid K-Cl co-transporters alters erythrocyte volume and partially rescues erythrocyte dehydration in SAD mice. J Clin Invest 117, 1708-17, 2007

Jacobs S., Ruusuvuori E., Sipilä S., Hapaanen A., Damkier H.H., Kurth I., Hentschke M., Schweizer M., Rudhard Y., Laatinkainen L., Tyynelä J., Praetorius J., Voipio J., Hübner C.A. Targeted gene disruption of Slc4a10 results in reduced brain ventricle size and dampens neuronal excitability. Proc Natl Acad Sci U S A 105, 311-6, 2008

Pfeffer C., Stein V., Keating D., Maier H., Rudhard Y., Hentschke M., Rune G., Jentsch T.J., Hübner C.A. GABA-dependent network activity contributes to early maturation of excitatory hippocampal synapses. J Neurosci 29, 3419-30, 2009

Leviel F*, Hübner* CA, Morla L, Houillier P, El Moghrabi S, Brideau G, Hatim H, Kurth I, Kougioumtzes A, Sinning A, Pech V, Riemondy KA, Miller RL, Hummler E, Shull GE, Aronson PS, Doucet A, Wall SM, Chambrey R, and Eladari D (2010) Identification of a novel amiloride-resistant, thiazide-sensitive NaCl reabsorption pathway in the distal nephron. J Clin Invest 120, 1627-1635  *equally contributing






Neurodegeneration / Hereditary Axonopathies





The axon is the long process of a neuron that carries efferent action potentials from the soma to the target cell. Because protein and lipid synthesis largely occur in the cell soma, anterograde transport is required to supply axons with the respective materials. Conversely, material intended for degradation has to be transported in a retrograde manner to the cell soma. The same logistic challenge applies to intracellular signals, both anterogradely and retrogradely. Thus, it is no surprise that neurons with long projections are particularly susceptible to impairment in cell processes such as trafficking, transport, energy utilization, signalling and cytoskeletal organization. The term axonopathy refers to a group of neurodegenerative disorders that mainly manifests at long axons as e.g. hereditary spastic paraplegia (HSP), amyotrophic lateral sclerosis (ALS), hereditary motor and sensory neuropathies (CMT/HMSN), and hereditary sensory and autonomic neuropathies (HSAN). Our current research focus in the field is to investigate the genetic and cell-biological basis of disease in selected axonopathies.



Selected Publications:


Kurth I, Pamminger T , Hennings JC, Soehendra D, Huebner AK, Rotthier A, Baets J, Senderek J, Topaloglu H, Farrell SA, Nürnberg G, Nürnberg P, De Jonghe P, Gal A, Kaether C, Timmerman V, Hübner CA. Mutations in FAM134B, encoding a novel Golgi protein, cause severe sensory and autonomic neuropathy. Nature Genetics 2009 Nov;41(11):1179-81.

Kurth I. Verlust des Sensibilitäts- und Schmerzempfindens - Hereditäre Sensorisch-Autonome Neuropathien (HSAN), Medizinische Genetik 2011;  23:15-20

Kurth I. Hereditary Sensory and Autonomic Neuropathy Type II, GeneReviews, in Pagon RA, Bird TD, Dolan CR, et al., editors. Seattle (WA):

Schüle R, Brandt E, Karle KN, Tsaousidou M, Klebe S, Klimpe S, Auer-Grumbach M, Crosby AH, Hübner CA, Schöls L, Deufel T, Beetz C. Analysis of CYP7B1 in non-consanguineous cases of hereditary spastic paraplegia. Neurogenetics. 2009 Apr;10(2):97-104.

Poët M, Kornak U, Schweizer M, Zdebik AA, Scheel O, Hoelter S, Wurst W, Schmitt A,  Fuhrmann JC, Planells-Cases R, Mole SE, Hübner CA, Jentsch TJ (2006). Lysosomal storage disease upon disruption of the neuronal chloride transport protein ClC-6. Proc Natl Acad Sci USA 103, 13854-13859

Boettger T., Rust M.B., Maier H., Seidenbecher T., Schweizer M., Keating D.J., Faulhaber J., Ehmke H., Pfeffer C., Scheel O., Lemcke B., Horst J., Leuwer R., Pape H.C., Völkl H., Hübner C.A., Jentsch T.J. (2003) Loss of K-Cl co-transporter KCC3 causes deafness, neurodegeneration and reduced seizure threshold. EMBO Journal 22, 5422-34






Identification of disease causative genes in human disorders






The identification of disease causative genes in human hereditary disorders is another focus of our work. Recently, we could identify mutations in the SMPX-gene in one form of X-chromosomal deafness. Other syndromes for which we were able to identify the molecular correlate of the disease included developmental bone disorders and neuronal migration defects. 



Selected Publications:


Huebner AK, Gandia M, Frommolt P, Maak A, Wicklein EM, Thiele H, Altmüller J, Wagner F, Viñuela A, Aguirre LA, Moreno F, Maier H, Rau I, Gießelmann S, Nürnberg G, Gal A, Nürnberg P, Hübner CA, del Castillo I, Kurth I. Nonsense mutations in SMPX, encoding a protein responsive to physical force, result in X-chromosomal hearing loss (DFNX4). Am J Hum Genet., accepted.

Lausch E, Janecke A, Bros M, Trojandt S, Alanay Y, De Laet C, Hübner CA, Meinecke P, Nishimura G, Matsuo M, Hirano Y, Tenoutasse S, Kiss A, Rosa RF, Unger SL, Renella R, Bonafé L, Spranger J, Unger S, Zabel B, Superti-Furga A (2011). Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity. Nat Genet 143, 132-137

Kim HG, Ahn JW, Kurth I, Ullmann R, Kim HT, Kulharya A, Ha KS, Itokawa Y, Meliciani I, Wenzel W, Lee D, Rosenberger G, Ozata M, Bick DP, Sherins RJ, Nagase T, Tekin M, Kim SH, Kim CH, Ropers HH, Gusella JF, Kalscheuer V, Choi CY, Layman LC (2010). WDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Am J Hum Genet. 87(4):465-79.

Kurth I, Klopocki E, Stricker S, van Oosterwijk J, Vanek S, Altmann J, Santos HG, van Harssel J, de Ravel T, Wilkie AOM, Gal A, Mundlos S. Duplications of non-coding elements 5´ of SOX9 are associated with brachydactyly/anonychia. Nature Genetics 2009 Aug;41(8):862-3

Kim HG, Kurth I, Lan F, Meliciani I, Wenzel W, Eom SH, Kang GB, Rosenberger G, Tekin M, Ozata M, Bick DP, Sherins RJ, Walker SL, Shi Y, Gusella JF, Layman LC. Mutations in CHD7, encoding a chromatin-remodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome (2008). Am J Hum Genet. 2008 Oct;83(4):511-9

Janecke AR, Thompson DA, Utermann G, Becker C, Hübner CA, Schmid E, McHenry CL, Nair AR, Ruschendorf F, Heckenlively J, Wissinger B, Nurnberg P, Gal A (2004). Mutations in RDH12 encoding a photoreceptor cell retinol dehydrogenase cause severe childhood-onset retinal dystrophy. Nature Genetics 36, 850-4, 2004











"Regulation of endoplasmic reticulum turnover by selective autophagy"

-> Nature, June 2015

see also:-> "News and Views"


"GABAergic regulation of cerebellar NG2 cell development is altered in perinatal white matter injury"

-> Nat Neurosci, May 2015


 "A de novo gain-of-function mutation in SCN11A causes loss of pain perception"

-> Nature Genetics, Sep 2013

see also: "News and Views" in Nat Genet


"A causative link between inner ear defects and long-term striatal dysfunction"

-> Science, 2013, Sep 2013
see also: Editor´s choice


"Mutations in GMPPA Cause a Glycosylation Disorder Characterized by Intellectual Disability and Autonomic Dysfunction"

-> AJHG, Sep 2013


"A hereditary spastic paraplegia mouse model reveals Reep1-dependent ER shaping"

-> JCI, Sep 2013

see also: Commentary in JCI