A novel heterozygous GLI2 mutation in a patient with congenital urethral stricture and renal hypoplasia/dysplasia leading to end-stage renal failure

Abstract

Glioblastoma 2 (GLI2) is a mediator of Sonic hedgehog signaling pathway that plays an important role in development of the central nervous system and limbs. Heterozygous GLI2 mutations have been associated with postaxial polydactyly, various pituitary dysfunction, and holoprosencephaly-like phenotype. Herein, we report a Japanese boy who presented with isolated growth hormone deficiency with ectopic posterior pituitary, postaxial polydactyly, atrioventricular septal defect, intellectual disability and dysmorphic facial features including mid-facial hypoplasia. The patient was also complicated with congenital urethral stricture with megacystis, hydronephrosis, and renal hypoplasia/dysplasia, which led to end-stage renal failure by the age of 8 years. Trio-whole-exome sequencing showed a novel de novo heterozygous frameshift mutation in GLI2 (c.3369delG, p.Met1123Ilefs*7) in the patient. This is the first report of possible association between GLI2 mutation and the phenotype of congenital anomalies of the kidney and urinary tract, and subsequent end-stage renal failure. Further studies on the urogenital phenotype in patients with GLI2 mutations may clarify a role of GLI2 in embryonic development of the urinary tract.

Keywords: CAKUT; GH deficiency; GLI2; Polydactyly; Renal failure; Urethral stricture.

Fig. 1

Clinical and genetic findings in the patient. a Postaxial polydactyly. b Voiding cystourethrography at 4 years of age showed megacystis and high-grade left vesicoureteral reflux. c Magnetic resonance imaging of brain showed ectopic posterior pituitary and anterior pituitary hypoplasia. d Electrochromatogram of the GLI2 gene in the patient. Wild-type and mutant sequences are shown. e The structure of GLI2 and the position of the mutation (black arrow). The black and white boxes on the genomic DNA (gDNA) denote the coding regions on exons 1–14 and the untranslated regions, respectively. The black arrow and the dashed line indicate positions of the mutation and the produced stop codon, respectively. DBD DNA-binding domain, TA transactivation domain