Requirement of FAT and DCHS protocadherins during hypothalamic-pituitary development

Emily J Lodge; Paraskevi Xekouki; Tatiane S Silva; Cristiane Kochi; Carlos A Longui; Fabio R Faucz; Alice Santambrogio; James L Mills; Nathan Pankratz; John Lane; Dominika Sosnowska; Tina Hodgson; Amanda L Patist; Philippa Francis-West; Francoise Helmbacher; Constantine Stratakis; Cynthia L Andoniadou

doi:10.1172/jci.insight.134310

Requirement of FAT and DCHS protocadherins during hypothalamic-pituitary development

Emily J Lodge, Paraskevi Xekouki, Tatiane S Silva, Cristiane Kochi, Carlos A Longui, Fabio R Faucz, Alice Santambrogio, James L Mills, Nathan Pankratz, John Lane, Dominika Sosnowska, Tina Hodgson, Amanda L Patist, Philippa Francis-West, Francoise Helmbacher, Constantine Stratakis, Cynthia L Andoniadou

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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 for mutations in the FAT/DCHS family of protocadherins that have high functional redundancy. We identified 7 variants, 4 of which are putatively damaging, in FAT2 and DCHS2 in 6 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 2 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 anterior pituitary cell types. 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
Article number	e134310
Journal	JCI Insight
Volume	5
Issue number	23
DOIs	https://doi.org/10.1172/jci.insight.134310
Publication status	Published - 3 Dec 2020

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10.1172/jci.insight.134310

Lodge et al JCI Isight 2020Licence: CC BY

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Lodge, E. J., Xekouki, P., Silva, T. S., Kochi, C., Longui, C. A., Faucz, F. R., Santambrogio, A., Mills, J. L., Pankratz, N., Lane, J., Sosnowska, D., Hodgson, T., Patist, A. L., Francis-West, P., Helmbacher, F., Stratakis, C., & Andoniadou, C. L. (2020). Requirement of FAT and DCHS protocadherins during hypothalamic-pituitary development. JCI Insight, 5(23), Article e134310. https://doi.org/10.1172/jci.insight.134310

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title = "Requirement of FAT and DCHS protocadherins during hypothalamic-pituitary development",

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 for mutations in the FAT/DCHS family of protocadherins that have high functional redundancy. We identified 7 variants, 4 of which are putatively damaging, in FAT2 and DCHS2 in 6 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 2 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 anterior pituitary cell types. 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. ",

author = "Lodge, {Emily J} and Paraskevi Xekouki and Silva, {Tatiane S} and Cristiane Kochi and Longui, {Carlos A} and Faucz, {Fabio R} and Alice Santambrogio and Mills, {James L} and Nathan Pankratz and John Lane and Dominika Sosnowska and Tina Hodgson and Patist, {Amanda L} and Philippa Francis-West and Francoise Helmbacher and Constantine Stratakis and Andoniadou, {Cynthia L}",

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doi = "10.1172/jci.insight.134310",

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Lodge, EJ, Xekouki, P, Silva, TS, Kochi, C, Longui, CA, Faucz, FR, Santambrogio, A, Mills, JL, Pankratz, N, Lane, J, Sosnowska, D , Hodgson, T , Patist, AL , Francis-West, P, Helmbacher, F, Stratakis, C & Andoniadou, CL 2020, 'Requirement of FAT and DCHS protocadherins during hypothalamic-pituitary development', JCI Insight, vol. 5, no. 23, e134310. https://doi.org/10.1172/jci.insight.134310

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T1 - Requirement of FAT and DCHS protocadherins during hypothalamic-pituitary development

AU - Lodge, Emily J

AU - Xekouki, Paraskevi

AU - Silva, Tatiane S

AU - Kochi, Cristiane

AU - Longui, Carlos A

AU - Faucz, Fabio R

AU - Santambrogio, Alice

AU - Mills, James L

AU - Pankratz, Nathan

AU - Lane, John

AU - Sosnowska, Dominika

AU - Hodgson, Tina

AU - Patist, Amanda L

AU - Francis-West, Philippa

AU - Helmbacher, Francoise

AU - Stratakis, Constantine

AU - Andoniadou, Cynthia L

PY - 2020/12/3

Y1 - 2020/12/3

N2 - 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 for mutations in the FAT/DCHS family of protocadherins that have high functional redundancy. We identified 7 variants, 4 of which are putatively damaging, in FAT2 and DCHS2 in 6 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 2 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 anterior pituitary cell types. 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.

AB - 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 for mutations in the FAT/DCHS family of protocadherins that have high functional redundancy. We identified 7 variants, 4 of which are putatively damaging, in FAT2 and DCHS2 in 6 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 2 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 anterior pituitary cell types. 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.

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U2 - 10.1172/jci.insight.134310

DO - 10.1172/jci.insight.134310

M3 - Article

C2 - 33108146

SN - 2379-3708

VL - 5

JO - JCI Insight

JF - JCI Insight

IS - 23

M1 - e134310

ER -

Requirement of FAT and DCHS protocadherins during hypothalamic-pituitary development

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