A patient with combined pituitary hormone deficiency and osteogenesis imperfecta associated with mutations in LHX4 and COL1A2
Genetic disorders have been shown to co-occur in individual patient. A Thai boy with features of osteogenesis imperfecta (OI) and combined pituitary hormone deficiency (CPHD) was identified. The causative mutations were investigated by whole exome and Sanger sequencing. Pathogenicity and pathomechan...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-01-01
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| Series: | Journal of Advanced Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S209012321930164X |
| _version_ | 1828815057847320576 |
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| author | Nalinee Hemwong Chureerat Phokaew Chalurmpon Srichomthong Siraprapa Tongkobpetch Khomsak Srilanchakon Vichit Supornsilchai Kanya Suphapeetiporn Thantrira Porntaveetus Vorasuk Shotelersuk |
| author_facet | Nalinee Hemwong Chureerat Phokaew Chalurmpon Srichomthong Siraprapa Tongkobpetch Khomsak Srilanchakon Vichit Supornsilchai Kanya Suphapeetiporn Thantrira Porntaveetus Vorasuk Shotelersuk |
| author_sort | Nalinee Hemwong |
| collection | DOAJ |
| description | Genetic disorders have been shown to co-occur in individual patient. A Thai boy with features of osteogenesis imperfecta (OI) and combined pituitary hormone deficiency (CPHD) was identified. The causative mutations were investigated by whole exome and Sanger sequencing. Pathogenicity and pathomechanism of the variants were studied by luciferase assay. The proband was found to harbor a novel de novo heterozygous missense mutation, c.1531G > T (p.G511C), in COL1A2 leading to OI and a heterozygous missense variant, c.364C > T (p.R122W), in LHX4. The LHX4 p.R122W has never been reported to cause CPHD. The variant was predicted to be deleterious and found in the highly conserved LIM2 domain of LHX4. The luciferase assays revealed that the p.R122W was unable to activate POU1F1, GH1, and TSHB promoters, validating its pathogenic effect in CPHD. Moreover, the variant did not alter the function of wild-type LHX4, indicating its hypomorphic pathomechanism. In conclusion, the novel de novo heterozygous p.G511C mutation in COL1A2 and the heterozygous pathogenic p.R122W mutation in LHX4 were demonstrated in a patient with OI and CPHD. This study proposes that the mutations in two different genes should be sought in the patients with clinical features unable to be explained by a mutation in one gene. Keywords: Thyroxine, Bisphosphonate, Mutation, Insulin, Skeleton, Growth |
| first_indexed | 2024-12-12T10:37:05Z |
| format | Article |
| id | doaj.art-9c628ad41fed4751862f3a3a2beea119 |
| institution | Directory Open Access Journal |
| issn | 2090-1232 |
| language | English |
| last_indexed | 2024-12-12T10:37:05Z |
| publishDate | 2020-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Advanced Research |
| spelling | doaj.art-9c628ad41fed4751862f3a3a2beea1192022-12-22T00:27:10ZengElsevierJournal of Advanced Research2090-12322020-01-0121121127A patient with combined pituitary hormone deficiency and osteogenesis imperfecta associated with mutations in LHX4 and COL1A2Nalinee Hemwong0Chureerat Phokaew1Chalurmpon Srichomthong2Siraprapa Tongkobpetch3Khomsak Srilanchakon4Vichit Supornsilchai5Kanya Suphapeetiporn6Thantrira Porntaveetus7Vorasuk Shotelersuk8Medical Sciences Program, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand; Center of Excellence for Regenerative Dentistry, Faculty of Dentistry, Chulalongkorn University, Bangkok, 10330, ThailandCenter of Excellence for Medical Genomics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand; Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, 10330, ThailandCenter of Excellence for Medical Genomics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand; Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, 10330, ThailandCenter of Excellence for Medical Genomics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand; Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, 10330, ThailandDivision of Endocrinology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, ThailandDivision of Endocrinology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, ThailandExcellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, 10330, Thailand; Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, 10330, ThailandGenomics and Precision Dentistry Research Unit, Department of Physiology, Faculty of Dentistry, Chulalongkorn University, Bangkok, 10330, Thailand; Corresponding author at: Genomics and Precision Dentistry Research Unit, Department of Physiology, Faculty of Dentistry, Chulalongkorn University, Bangkok 10330, Thailand.Center of Excellence for Medical Genomics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand; Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, 10330, ThailandGenetic disorders have been shown to co-occur in individual patient. A Thai boy with features of osteogenesis imperfecta (OI) and combined pituitary hormone deficiency (CPHD) was identified. The causative mutations were investigated by whole exome and Sanger sequencing. Pathogenicity and pathomechanism of the variants were studied by luciferase assay. The proband was found to harbor a novel de novo heterozygous missense mutation, c.1531G > T (p.G511C), in COL1A2 leading to OI and a heterozygous missense variant, c.364C > T (p.R122W), in LHX4. The LHX4 p.R122W has never been reported to cause CPHD. The variant was predicted to be deleterious and found in the highly conserved LIM2 domain of LHX4. The luciferase assays revealed that the p.R122W was unable to activate POU1F1, GH1, and TSHB promoters, validating its pathogenic effect in CPHD. Moreover, the variant did not alter the function of wild-type LHX4, indicating its hypomorphic pathomechanism. In conclusion, the novel de novo heterozygous p.G511C mutation in COL1A2 and the heterozygous pathogenic p.R122W mutation in LHX4 were demonstrated in a patient with OI and CPHD. This study proposes that the mutations in two different genes should be sought in the patients with clinical features unable to be explained by a mutation in one gene. Keywords: Thyroxine, Bisphosphonate, Mutation, Insulin, Skeleton, Growthhttp://www.sciencedirect.com/science/article/pii/S209012321930164X |
| spellingShingle | Nalinee Hemwong Chureerat Phokaew Chalurmpon Srichomthong Siraprapa Tongkobpetch Khomsak Srilanchakon Vichit Supornsilchai Kanya Suphapeetiporn Thantrira Porntaveetus Vorasuk Shotelersuk A patient with combined pituitary hormone deficiency and osteogenesis imperfecta associated with mutations in LHX4 and COL1A2 Journal of Advanced Research |
| title | A patient with combined pituitary hormone deficiency and osteogenesis imperfecta associated with mutations in LHX4 and COL1A2 |
| title_full | A patient with combined pituitary hormone deficiency and osteogenesis imperfecta associated with mutations in LHX4 and COL1A2 |
| title_fullStr | A patient with combined pituitary hormone deficiency and osteogenesis imperfecta associated with mutations in LHX4 and COL1A2 |
| title_full_unstemmed | A patient with combined pituitary hormone deficiency and osteogenesis imperfecta associated with mutations in LHX4 and COL1A2 |
| title_short | A patient with combined pituitary hormone deficiency and osteogenesis imperfecta associated with mutations in LHX4 and COL1A2 |
| title_sort | patient with combined pituitary hormone deficiency and osteogenesis imperfecta associated with mutations in lhx4 and col1a2 |
| url | http://www.sciencedirect.com/science/article/pii/S209012321930164X |
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