Copy Number Variants Contributing to Combined Pituitary Hormone Deficiency
Abstract
:1. Introduction
2. Patients
3. Methods
Filtering Genomic Data
4. Results
5. Discussion
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Duquesnoy, P.; Roy, A.; Dastot, F.; Ghali, I.; Teinturier, C.; Netchine, I.; Cacheux, V.; Hafez, M.; Salah, N.; Chaussain, J.L.; et al. Human prop-1: Cloning, mapping, genomic structure. Mutations in familial combined pituitary hormone deficiency. FEBS Lett. 1998, 437, 216–220. [Google Scholar] [CrossRef] [Green Version]
- Fluck, C.; Deladoey, J.; Rutishauser, K.; Eble, A.; Marti, U.; Wu, W.; Mullis, P.E. Phenotypic variability in familial combined pituitary hormone deficiency caused by a prop1 gene mutation resulting in the substitution of arg→cys at codon 120 (r120c). J. Clin. Endocrinol. Metab. 1998, 83, 3727–3734. [Google Scholar] [CrossRef] [PubMed]
- Wu, W.; Cogan, J.D.; Pfaffle, R.W.; Dasen, J.S.; Frisch, H.; O’Connell, S.M.; Flynn, S.E.; Brown, M.R.; Mullis, P.E.; Parks, J.S.; et al. Mutations in prop1 cause familial combined pituitary hormone deficiency. Nat. Genet. 1998, 18, 147–149. [Google Scholar] [CrossRef] [PubMed]
- Kim, S.S.; Kim, Y.; Shin, Y.L.; Kim, G.H.; Kim, T.U.; Yoo, H.W. Clinical characteristics and molecular analysis of pit1, prop1,lhx3, and hesx1 in combined pituitary hormone deficiency patients with abnormal pituitary mr imaging. Horm. Res. 2003, 60, 277–283. [Google Scholar] [CrossRef]
- Davis, S.W.; Ellsworth, B.S.; Perez Millan, M.I.; Gergics, P.; Schade, V.; Foyouzi, N.; Brinkmeier, M.L.; Mortensen, A.H.; Camper, S.A. Pituitary gland development and disease: From stem cell to hormone production. Curr. Top. Dev. Biol. 2013, 106, 1–47. [Google Scholar]
- Ellsworth, B.S.; Stallings, C.E. Molecular mechanisms governing embryonic differentiation of pituitary somatotropes. Trends Endocrinol. Metab. TEM 2018, 29, 510–523. [Google Scholar] [CrossRef]
- Perez Millan, M.I.; Vishnopolska, S.A.; Daly, A.Z.; Bustamante, J.P.; Seilicovich, A.; Bergada, I.; Braslavsky, D.; Keselman, A.C.; Lemons, R.M.; Mortensen, A.H.; et al. Next generation sequencing panel based on single molecule molecular inversion probes for detecting genetic variants in children with hypopituitarism. Mol. Genet. Genom. Med. 2018, 6, 514–525. [Google Scholar] [CrossRef]
- Zwaveling-Soonawala, N.; Alders, M.; Jongejan, A.; Kovacic, L.; Duijkers, F.A.; Maas, S.M.; Fliers, E.; van Trotsenburg, A.S.P.; Hennekam, R.C. Clues for polygenic inheritance of pituitary stalk interruption syndrome from exome sequencing in 20 patients. J. Clin. Endocrinol. Metab. 2018, 103, 415–428. [Google Scholar] [CrossRef] [Green Version]
- Guo, Q.H.; Wang, C.Z.; Wu, Z.Q.; Qin, Y.; Han, B.Y.; Wang, A.P.; Wang, B.A.; Dou, J.T.; Wu, X.S.; Mu, Y.M. Multi-genic pattern found in rare type of hypopituitarism: A whole-exome sequencing study of han chinese with pituitary stalk interruption syndrome. J. Cell. Mol. Med. 2017, 21, 3626–3632. [Google Scholar] [CrossRef] [Green Version]
- Fang, Q.; George, A.S.; Brinkmeier, M.L.; Mortensen, A.H.; Gergics, P.; Cheung, L.Y.; Daly, A.Z.; Ajmal, A.; Perez Millan, M.I.; Ozel, A.B.; et al. Genetics of combined pituitary hormone deficiency: Roadmap into the genome era. Endocr. Rev. 2016, 37, 636–675. [Google Scholar] [CrossRef] [Green Version]
- Vetro, A.; Pagani, S.; Silengo, M.; Severino, M.; Bozzola, E.; Meazza, C.; Zuffardi, O.; Bozzola, M. Severe growth hormone deficiency and pituitary malformation in a patient with chromosome 2p25 duplication and 2q37 deletion. Mol. Cytogenet. 2014, 7, 41. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- El Chehadeh-Djebbar, S.; Callier, P.; Masurel-Paulet, A.; Bensignor, C.; Mejean, N.; Payet, M.; Ragon, C.; Durand, C.; Marle, N.; Mosca-Boidron, A.L.; et al. 17q21.31 microdeletion in a patient with pituitary stalk interruption syndrome. Eur. J. Med. Genet. 2011, 54, 369–373. [Google Scholar] [CrossRef] [PubMed]
- Bauters, M.; Frints, S.G.; Van Esch, H.; Spruijt, L.; Baldewijns, M.M.; de Die-Smulders, C.E.; Fryns, J.P.; Marynen, P.; Froyen, G. Evidence for increased sox3 dosage as a risk factor for x-linked hypopituitarism and neural tube defects. Am. J. Med. Genet. A 2014, 164A, 1947–1952. [Google Scholar] [CrossRef] [PubMed]
- Woods, K.S.; Cundall, M.; Turton, J.; Rizotti, K.; Mehta, A.; Palmer, R.; Wong, J.; Chong, W.K.; Al-Zyoud, M.; El-Ali, M.; et al. Over- and underdosage of sox3 is associated with infundibular hypoplasia and hypopituitarism. Am. J. Hum. Genet. 2005, 76, 833–849. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Correa, F.A.; Jorge, A.A.; Nakaguma, M.; Canton, A.P.; Costa, S.S.; Funari, M.F.; Lerario, A.M.; Franca, M.M.; Carvalho, L.R.; Krepischi, A.C.; et al. Pathogenic copy number variants in patients with congenital hypopituitarism associated with complex phenotypes. Clin. Endocrinol. 2018, 88, 425–431. [Google Scholar] [CrossRef]
- Budny, B.; Zemojtel, T.; Kaluzna, M.; Gut, P.; Niedziela, M.; Obara-Moszynska, M.; Rabska-Pietrzak, B.; Karmelita-Katulska, K.; Stajgis, M.; Ambroziak, U.; et al. Sema3a and igsf10 are novel contributors to combined pituitary hormone deficiency (cphd). Front. Endocrinol. 2020, 11, 368. [Google Scholar] [CrossRef]
- Ziemnicka, K.; Gut, P.; Golab, M.; Dworacki, G.; Wrotkowska, E.; Stajgis, M.; Katulska, K.; Rabska-Pietrzak, B.; Obara-Moszynska, M.; Niedziela, M.; et al. Pituitary microsomal autoantibodies in patients with childhood-onset combined pituitary hormone deficiency: An antigen identification attempt. Arch. Immunol. Ther. Exp. 2016, 64, 485–495. [Google Scholar] [CrossRef] [Green Version]
- Davis, S.W.; Castinetti, F.; Carvalho, L.R.; Ellsworth, B.S.; Potok, M.A.; Lyons, R.H.; Brinkmeier, M.L.; Raetzman, L.T.; Carninci, P.; Mortensen, A.H.; et al. Molecular mechanisms of pituitary organogenesis: In search of novel regulatory genes. Mol. Cell. Endocrinol. 2010, 323, 4–19. [Google Scholar] [CrossRef] [Green Version]
- Budny, B.; Szczepanek-Parulska, E.; Zemojtel, T.; Szaflarski, W.; Rydzanicz, M.; Wesoly, J.; Handschuh, L.; Wolinski, K.; Piatek, K.; Niedziela, M.; et al. Mutations in proteasome-related genes are associated with thyroid hemiagenesis. Endocrine 2017, 56, 279–285. [Google Scholar] [CrossRef] [Green Version]
- Rogers, K.W.; Schier, A.F. Morphogen gradients: From generation to interpretation. Annu. Rev. Cell Dev. Biol. 2011, 27, 377–407. [Google Scholar] [CrossRef] [Green Version]
- Hirt, N.; Eggermann, K.; Hyrenbach, S.; Lambeck, J.; Busche, A.; Fischer, J.; Rudnik-Schoneborn, S.; Gaspar, H. Genetic dosage compensation via co-occurrence of pmp22 duplication and pmp22 deletion. Neurology 2015, 84, 1605–1606. [Google Scholar] [CrossRef] [PubMed]
- Zhao, L.; Zevallos, S.E.; Rizzoti, K.; Jeong, Y.; Lovell-Badge, R.; Epstein, D.J. Disruption of soxb1-dependent sonic hedgehog expression in the hypothalamus causes septo-optic dysplasia. Dev. Cell 2012, 22, 585–596. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Camper, S.A.; Daly, A.Z.; Stallings, C.E.; Ellsworth, B.S. Hypothalamic beta-catenin is essential for fgf8-mediated anterior pituitary growth: Links to human disease. Endocrinology 2017, 158, 3322–3324. [Google Scholar] [CrossRef] [PubMed]
- Osmundsen, A.M.; Keisler, J.L.; Taketo, M.M.; Davis, S.W. Canonical wnt signaling regulates the pituitary organizer and pituitary gland formation. Endocrinology 2017, 158, 3339–3353. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sobrier, M.L.; Attie-Bitach, T.; Netchine, I.; Encha-Razavi, F.; Vekemans, M.; Amselem, S. Pathophysiology of syndromic combined pituitary hormone deficiency due to a lhx3 defect in light of lhx3 and lhx4 expression during early human development. Gene Expr. Patterns GEP 2004, 5, 279–284. [Google Scholar] [CrossRef] [PubMed]
- Machinis, K.; Pantel, J.; Netchine, I.; Leger, J.; Camand, O.J.; Sobrier, M.L.; Dastot-Le Moal, F.; Duquesnoy, P.; Abitbol, M.; Czernichow, P.; et al. Syndromic short stature in patients with a germline mutation in the lim homeobox lhx4. Am. J. Hum. Genet. 2001, 69, 961–968. [Google Scholar] [CrossRef] [Green Version]
- Pfaeffle, R.W.; Hunter, C.S.; Savage, J.J.; Duran-Prado, M.; Mullen, R.D.; Neeb, Z.P.; Eiholzer, U.; Hesse, V.; Haddad, N.G.; Stobbe, H.M.; et al. Three novel missense mutations within the lhx4 gene are associated with variable pituitary hormone deficiencies. J. Clin. Endocrinol. Metab. 2008, 93, 1062–1071. [Google Scholar] [CrossRef]
- Castinetti, F.; Saveanu, A.; Reynaud, R.; Quentien, M.H.; Buffin, A.; Brauner, R.; Kaffel, N.; Albarel, F.; Guedj, A.M.; El Kholy, M.; et al. A novel dysfunctional lhx4 mutation with high phenotypical variability in patients with hypopituitarism. J. Clin. Endocrinol. Metab. 2008, 93, 2790–2799. [Google Scholar] [CrossRef] [Green Version]
- Tajima, T.; Ohtake, A.; Hoshino, M.; Amemiya, S.; Sasaki, N.; Ishizu, K.; Fujieda, K. Otx2 loss of function mutation causes anophthalmia and combined pituitary hormone deficiency with a small anterior and ectopic posterior pituitary. J. Clin. Endocrinol. Metab. 2009, 94, 314–319. [Google Scholar] [CrossRef] [Green Version]
- Dateki, S.; Kosaka, K.; Hasegawa, K.; Tanaka, H.; Azuma, N.; Yokoya, S.; Muroya, K.; Adachi, M.; Tajima, T.; Motomura, K.; et al. Heterozygous orthodenticle homeobox 2 mutations are associated with variable pituitary phenotype. J. Clin. Endocrinol. Metab. 2010, 95, 756–764. [Google Scholar] [CrossRef] [Green Version]
- Oliver, G.; Mailhos, A.; Wehr, R.; Copeland, N.G.; Jenkins, N.A.; Gruss, P. Six3, a murine homologue of the sine oculis gene, demarcates the most anterior border of the developing neural plate and is expressed during eye development. Development 1995, 121, 4045–4055. [Google Scholar] [PubMed]
- Wallis, D.E.; Roessler, E.; Hehr, U.; Nanni, L.; Wiltshire, T.; Richieri-Costa, A.; Gillessen-Kaesbach, G.; Zackai, E.H.; Rommens, J.; Muenke, M. Mutations in the homeodomain of the human six3 gene cause holoprosencephaly. Nat. Genet. 1999, 22, 196–198. [Google Scholar] [CrossRef] [PubMed]
- Anchan, R.M.; Lachke, S.A.; Gerami-Naini, B.; Lindsey, J.; Ng, N.; Naber, C.; Nickerson, M.; Cavallesco, R.; Rowan, S.; Eaton, J.L.; et al. Pax6- and six3-mediated induction of lens cell fate in mouse and human es cells. PLoS ONE 2014, 9, e115106. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Xie, H.; Hoffmann, H.M.; Meadows, J.D.; Mayo, S.L.; Trang, C.; Leming, S.S.; Maruggi, C.; Davis, S.W.; Larder, R.; Mellon, P.L. Homeodomain proteins six3 and six6 regulate gonadotrope-specific genes during pituitary development. Mol. Endocrinol. 2015, 29, 842–855. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gaston-Massuet, C.; Andoniadou, C.L.; Signore, M.; Sajedi, E.; Bird, S.; Turner, J.M.; Martinez-Barbera, J.P. Genetic interaction between the homeobox transcription factors hesx1 and six3 is required for normal pituitary development. Dev. Biol. 2008, 324, 322–333. [Google Scholar] [CrossRef] [Green Version]
- Sajedi, E.; Gaston-Massuet, C.; Signore, M.; Andoniadou, C.L.; Kelberman, D.; Castro, S.; Etchevers, H.C.; Gerrelli, D.; Dattani, M.T.; Martinez-Barbera, J.P. Analysis of mouse models carrying the i26t and r160c substitutions in the transcriptional repressor hesx1 as models for septo-optic dysplasia and hypopituitarism. Dis. Models Mech. 2008, 1, 241–254. [Google Scholar] [CrossRef]
- Gaston-Massuet, C.; Kelberman, D.; Dattani, M.; Martinez-Barbera, J.P. Absence of six3 mutations in patients with congenital hypopituitarism. Am. J. Med. Genet. A 2009, 149A, 2874–2876. [Google Scholar] [CrossRef]
Patient | Type | Cytoband | Size (Kbp) | Gene Number | Gene Name | HGVS |
---|---|---|---|---|---|---|
1 | Loss | 1q22 | 54.284 | 2 | ASH1L, POU5F1P4 | arr[hg19] 1q22(155,394,484-155,448,768)x1 |
2 | Gain | 1q25.2 | 95.535 | 4 | QSOX1, FLJ23867, LHX4, LOC100527964 | arr[hg19] 1q25.2(180,143,701-180,239,236)x3 |
3 | Gain | 2p21 | 23.746 | 1 | SIX3 | arr[hg19] 2p21(45,151,117-45,174,863)x3 |
4 | Gain | 2p21 | 27.832 | 1 | SIX3 | arr[hg19] 2p21(45,151,117-45,178,949)x3 |
5 | Gain | 2p25.3 | 536.643 | 8 | TSSC1, TRAPPC12, ADI1, RNASEH1, LOC100506054, RPS7, COLEC11, ALLC | arr[hg19] 2p25.3(3,232,368-3,769,011)x3 |
6 | Gain | 2p25.3 | 475.292 | 8 | TSSC1, TRAPPC12, ADI1, RNASEH1, LOC100506054, RPS7, COLEC11, ALLC | arr[hg19] 2p25.3(3,339,014-3,814,306)x3 |
7 | Gain | 3p14.3 | 131.223 | 3 | IL17RD, HESX1, APPL1 | arr[hg19] 3p14.3(57,149,424-57,280,647)x3 |
8 | Gain | 14q22.3 | 46.766 | 2 | OTX2 | arr[hg19] 14q22.3(57251373-57298139)x3 |
9 | Gain | 14q22.3 | 47.781 | 2 | OTX2 | arr[hg19] 14q22.3(5763675-57311456)x3 |
10 | Gain | 14q22.3 | 24.896 | 2 | OTX2 | arr[hg19] 14q22.3(57263675-57288571)x3 |
11 | Loss | 18q12.3 | 373.468 | 1 | SLC14A2 | arr[hg19] 18q12.3(42,689,695-43,063,163)x1 |
12 | Loss | 18q12.3 | 390.92 | 1 | SLC14A2 | arr[hg19] 18q12.3(42,681,091-43,072,011)x1 |
Case | Gene(s) | Gender | Age at Diagnosis | Pituitary Hormone Deficiency | MRI of Pituitary | ||||
---|---|---|---|---|---|---|---|---|---|
GH | Gn | TSH | PRL | ACTH | |||||
1 | ASH1L, POU5F1P4 | M | 13 y.o. | + | + | + | − | + | Pituitary hypoplasia |
2 | QSOX1, FLJ23867, LHX4, LOC100527964 | F | 9 y.o. | + | + | + | − | − | PSIS |
3 | SIX3 | M | 12 y.o | + | + | + | − | + | Pituitary hypoplasia |
4 | SIX3 | M | 15 y.o | + | + | + | + | + | Pituitary hypoplasia |
5 | TSSC1, TRAPPC12, ADI1, RNASEH1, LOC100506054, RPS7, COLEC11, ALLC | M | 12 y.o | + | + | + | − | − | Pituitary hypoplasia |
6 | TSSC1, TRAPPC12, ADI1, RNASEH1, LOC100506054, RPS7, COLEC11, ALLC | F | 24 y.o. | + | + | + | − | − | PSIS |
7 | IL17RD, HESX1, APPL1 | M | 12 y.o. | + | + | + | − | + | Pituitary hypoplasia |
8 | OTX2 | F | 10 y.o. | + | + | + | − | + | PSIS |
9 | OTX2 | F | 6 y.o. | + | + | − | − | − | Pituitary hypoplasia |
10 | OTX2 | M | 15 y.o. | + | + | + | − | − | Pituitary hypoplasia |
11 | SLC14A2 | F | 8 y.o. | + | + | + | − | − | Pituitary hypoplasia |
12 | SLC14A2 | F | 8 y.o. | + | + | + | − | − | Pituitary hypoplasia |
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Budny, B.; Karmelita-Katulska, K.; Stajgis, M.; Żemojtel, T.; Ruchała, M.; Ziemnicka, K. Copy Number Variants Contributing to Combined Pituitary Hormone Deficiency. Int. J. Mol. Sci. 2020, 21, 5757. https://doi.org/10.3390/ijms21165757
Budny B, Karmelita-Katulska K, Stajgis M, Żemojtel T, Ruchała M, Ziemnicka K. Copy Number Variants Contributing to Combined Pituitary Hormone Deficiency. International Journal of Molecular Sciences. 2020; 21(16):5757. https://doi.org/10.3390/ijms21165757
Chicago/Turabian StyleBudny, Bartłomiej, Katarzyna Karmelita-Katulska, Marek Stajgis, Tomasz Żemojtel, Marek Ruchała, and Katarzyna Ziemnicka. 2020. "Copy Number Variants Contributing to Combined Pituitary Hormone Deficiency" International Journal of Molecular Sciences 21, no. 16: 5757. https://doi.org/10.3390/ijms21165757