Abstract
Pituitary developmental defects lead to partial or complete hormone deficiency and significant health problems. The majority of cases are sporadic and of unknown cause. We screened 28 patients with pituitary stalk interruption syndrome (PSIS) for mutations in the FAT/DCHS family of protocadherins that have high functional redundancy. We identified seven variants, four of which putatively damaging, in FAT2 and DCHS2 in six patients with pituitary developmental defects recruited through a cohort of patients with mostly ectopic posterior pituitary gland and/or pituitary stalk interruption. All patients had growth hormone deficiency and two presented with multiple hormone deficiencies and small glands. FAT2 and DCHS2 were strongly expressed in the mesenchyme surrounding the normal developing human pituitary. We analyzed Dchs2-/- mouse mutants and identified anterior pituitary hypoplasia and partially penetrant infundibular defects. Overlapping infundibular abnormalities and distinct anterior pituitary morphogenesis defects were observed in Fat4-/- and Dchs1-/- mouse mutants but all animal models displayed normal commitment to the anterior pituitary cell type. Together our data implicate FAT/DCHS protocadherins in normal hypothalamic-pituitary development and identify FAT2 and DCHS2 as candidates underlying pituitary gland developmental defects such as ectopic pituitary gland and/or pituitary stalk interruption.
| Original language | English (US) |
|---|---|
| Article number | e134310 |
| Journal | JCI Insight |
| Volume | 5 |
| Issue number | 23 |
| DOIs | |
| State | Published - Oct 27 2020 |
Bibliographical note
Funding Information:We thank the patients and their families for participating in the described studies. This study was supported by grants MR/L016729/1 from the Medical Research Council (to CLA), a Lister Institute Research Prize Fellowship to CLA, RG130699 from The Royal Society (to CLA), the Deutsche Forschungsgemeinschaft within the 314061271 - TRR 205 (to CLA), the AFM-T?l?thon (Association Fran?aise contre les myopathies) grant 20861 (to FH), and grant BB/M022544/1 from the Biotechnology and Biological Sciences Research Council (to PFW). This study was in part funded by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health of Human Development, NIH, Bethesda, Maryland, USA. We are grateful to Jacques Drouin and Simon Rhodes for TPIT and PIT antibodies, respectively, and the National Hormone and Peptide Program (Harbor-University of California, Los Angeles, Medical Center) for providing some of the hormone antibodies used in this study. We thank Kenneth Irvine for continued advice and sharing reagents and Helen McNeill for providing the Fat4 mouse mutant.
Funding Information:
We thank the patients and their families for participating in the described studies. This study was supported by grants MR/L016729/1 from the Medical Research Council (to CLA), a Lister Institute Research Prize Fellowship to CLA, RG130699 from The Royal Society (to CLA), the Deutsche Forschungsgemeinschaft within the 314061271 - TRR 205 (to CLA), the AFM-Téléthon (Association Française contre les myopathies) grant 20861 (to FH), and grant BB/M022544/1 from the Biotechnology and Biological Sciences Research Council (to PFW). This study was in part funded by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health of Human Development, NIH, Bethesda, Maryland, USA. We are grateful to Jacques Drouin and Simon Rhodes for TPIT and PIT antibodies, respectively, and the National Hormone and Peptide Program (Harbor-University of California, Los Angeles, Medical Center) for providing some of the hormone antibodies used in this study. We thank Kenneth Irvine for continued advice and sharing reagents and Helen McNeill for providing the Fat4 mouse mutant.
Publisher Copyright:
Copyright: © 2020, Lodge et al.