Diabetes, Associated Clinical Spectrum, Long-term Prognosis, and Genotype/Phenotype Correlations in 201 Adult Patients With Hepatocyte Nuclear Factor 1B (HNF1B) Molecular Defects

Abstract

In patients with HNF1B syndrome, diabetes complications, cardiovascular risk factors, CKD3-4, and ESRD are highly prevalent. At diabetes diagnosis, the presence of morphological and/or functional kidney disease may help etiological diagnosis. Genotype/phenotype correlations may have implications for the care and the prognosis of these patients.

Prenatal diagnosis of HNF1B‐associated renal cysts: Is there a need to differentiate intragenic variants from 17q12 microdeletion syndrome?

“…The neighboring residues Trp238 (cyan) and Lys237 (blue) are annotated as having a “specific DNA base contact[s]” or being involved in “DNA binding,” respectively (based on NCBI NP_000449.1). Additionally, the variant c.712T>C, p.(Trp238Arg), has been reported as pathogenic . The typical alpha‐helix breaker glycine at position 239 is located at the end of an alpha‐helix motif (residues 240‐252; purple), and its deletion (I1 described herein) or substitution likely disrupts the conformation and positioning of the AAs Lys237 and Trp238 required for DNA binding of the HNF1B transcription factor.…”

“…Two missense variants (c.715G>C, p.(Gly239Arg); and c.716G>A, p.(Gly239Glu)) affecting the same AA were reported in a boy with bilateral renal cysts, kidney failure, and diabetes in childhood and in a girl with MODY, renal cysts in the right kidney, agenesis of left kidney, and pancreas atrophy, respectively. Furthermore, a variant affecting the neighboring residue Trp238 (c.712T>C, p.(Trp238Arg)) was described as pathogenic (Figure ) . On the basis of the ACMG criteria ( de novo occurrence, no inclusion in population databases, previously described variant at the same position, affected highly conserved AA, and computationally indicated pathogenicity), we classified the identified variant as pathogenic (class 5).…”

“…Genetic variants affecting HNF1B are associated with multiple phenotypes . Aberrations of HNF1B were initially described as causative for maturity‐onset diabetes of the young type 5 (MODY5; MIM #137920) .…”

Comment on Dubois-Laforgue et al. Diabetes, Associated Clinical Spectrum, Long-term Prognosis, and Genotype/Phenotype Correlations in 201 Adult Patients With Hepatocyte Nuclear Factor 1B (HNF1B) Molecular Defects. Diabetes Care 2017;40:1436–1443

“…Both HNF1B deletion and truncating mutations would be expected to cause complete loss of a single allele. One hypothesis suggested by DuboisLaforgue et al (1) is that some intragenic HNF1B mutations may exert a dominant negative effect that results in a more severe phenotype. Although truncating mutations anywhere other than the terminal exon usually cause transcript degradation via the nonsense-mediated decay pathway (4), previous work has shown that there is a considerable variation in the degree of nonsense-mediated decay that is seen with different HNF1B mutations (5).…”

Primary male factor infertility due to asthenospermia in maturity-onset diabetes of the young type 5 (MODY 5): uncommon presentation of an uncommon disease

“…In a recently published large series of HNF1β syndrome involving 201 adult patients (mutations (n=101) or deletion (n=100)), abnormalities have been found in 16 of 20 males investigated specifically for genital tract anomalies. Seminal abnormalities have been detected in seven, epididymal cysts in four, cryptorchidism in three, varicocele in three, enlarged seminal vesicles in two and absent vas deferens in one of these individuals 13. The exact mechanism of asthenospermia in patients of MODY 5 is still unknown.…”