Standardized, systemic phenotypic analysis reveals kidney dysfunction as main alteration of Kctd1 I27N mutant mice

Abstract

BackgroundIncreased levels of blood plasma urea were used as phenotypic parameter for establishing novel mouse models for kidney diseases on the genetic background of C3H inbred mice in the phenotype-driven Munich ENU mouse mutagenesis project. The phenotypically dominant mutant line HST014 was established and further analyzed.MethodsAnalysis of the causative mutation as well as the standardized, systemic phenotypic analysis of the mutant line was carried out.ResultsThe causative mutation was detected in the potassium channel tetramerization domain containing 1 (Kctd1) gene which leads to the amino acid exchange Kctd1 I27N thereby affecting the functional BTB domain of the protein. This line is the first mouse model harboring a Kctd1 mutation. Kctd1 I27N homozygous mutant mice die perinatally. Standardized, systemic phenotypic analysis of Kctd1 I27N heterozygous mutants was carried out in the German Mouse Clinic (GMC). Systematic morphological investigation of the external physical appearance did not detect the specific alterations that are described in KCTD1 mutant human patients affected by the scalp-ear-nipple (SEN) syndrome. The main pathological phenotype of the Kctd1 I27N heterozygous mutant mice consists of kidney dysfunction and secondary effects thereof, without gross additional primary alterations in the other phenotypic parameters analyzed. Genome-wide transcriptome profiling analysis at the age of 4 months revealed about 100 differentially expressed genes (DEGs) in kidneys of Kctd1 I27N heterozygous mutants as compared to wild-type controls.ConclusionsIn summary, the main alteration of the Kctd1 I27N heterozygous mutants consists in kidney dysfunction. Additional analyses in 9–21 week-old heterozygous mutants revealed only few minor effects.Electronic supplementary materialThe online version of this article (doi:10.1186/s12929-017-0365-5) contains supplementary material, which is available to authorized users.

AP-2β/KCTD1 Control Distal Nephron Differentiation and Protect against Renal Fibrosis

“…Similarly, the in vivo role of KCTD1 in the kidney has remained unknown, in part due to the lack of KCTD1 null mice. Of note, a recent report described that a KCTD1 (I27N) mutation induced by ENU (N-ethyl-N-nitrosourea) mutagenesis resulted in perinatal lethality, and heterozygosity for this mutation resulted in increased BUN (Kumar et al, 2017). However, no further characterization of kidney function or histology were shown in this report, which also did not assess the effects of this mutation on KCTD1 activity.…”

Loss-of-function, gain-of-function and dominant-negative mutations have profoundly different effects on protein structure

“…However, not all DMS strategies are appropriate for different types of mutations. A recent study using fluorescent-coupled PTEN to measure the abundance of different variants was able to identify destabilising disease mutations, but not known DN mutations [72][73][74] . Future work will be required to determine the best ways to systematically identify pathogenic mutations associated with different molecular mechanisms using a DMS-like strategy.…”

KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders

“…Protein BTB structure Degrades c-Myc 29 Regulates sleep 86 Low in patient-derived glioma stem cells 29 Gen vars assoc. with Alzheimer's risk (GWAS) 110 Degrades RhoA 33,76 Regulates apoptosis 120 Inhibits NF-κB and AP-1 118 Aa a tumor suppressor in nonsmall cell lung cancer 121 Poor prognosis if overexpressed in breast cancer 122 Overexpressed in osteosarcoma 123 16,96 ) Inhibits mTORC1 activity 14 Inhibits Hh pathway by degrading HDAC 12 Deletion/ reduced expression in medulloblastoma 94 Loss of heterozygosity in prostate adenocarcinoma 129 Reduced expression in hepatocellular carcinoma 130 (Continues) Inhibits transcription factor AP-2α 9 and Wnt signaling by degrading β-catenin 131 I27N mutation caused kidney dysfunction in mice 132 Missense mutations associated with scalp-ear-nipple syndrome 133 Other Regulates GABA B2 signaling 17,135,136 ND Other KCNRG ND Kv channel 139,140 Suppresses K + channel activity 139 Deleted in B-cell chronic lymphocytic leukemia, [140][141][142] prostate cancer 140 and multiple myeloma 142 Other KCTD18 ND ND ND Duplication of 2q33 in one patient with epilepsy, devel. delay, autistic behavior 143 Haplotype associated with restless legs syndrome 144 G KCTD20 ND ND Activates Akt 145,146 Gen var associated with insulin resistance (GWAS) 147 BTBD10 ND Akt1-3 148 Inhibits apoptosis, activates Akt 149,150 Sporadic amyotrophic lateral sclerosis 151…”