Sclerosteosis : Report of type 1 or 2 in three Indian Tamil families and literature review
Copyright © 2018 Elsevier Inc. All rights reserved..
Sclerosteosis (SOST) refers to two extremely rare yet similar skeletal dysplasias featuring a diffusely radiodense skeleton together with congenital syndactyly. SOST1 is transmitted as an autosomal recessive (AR) trait and to date caused by ten homozygous loss-of-function mutations within the gene SOST that encodes the inhibitor of Wnt-mediated bone formation, sclerostin. SOST2 is transmitted as an autosomal dominant (AD) or AR trait and to date caused by one heterozygous or two homozygous loss-of-function mutation(s), respectively, within the gene LRP4 that encodes the sclerostin interaction protein, low-density lipoprotein receptor-related protein 4 (LRP4). Herein, we investigated two teenagers and one middle-aged man with SOST in three families living in the state of Tamil Nadu in southern India. Next generation sequencing of their genomic DNA using our high bone density gene panel revealed SOST1 in the teenagers caused by a unique homozygous nonsense SOST mutation (c.129C > G, p.Tyr43X) and SOST2 in the man caused by homozygosity for one of the two known homozygous missense LRP4 mutations (c.3508C > T, p.Arg1170Trp). He becomes the fourth individual and the first non-European recognized with SOST2. His clinical course was milder than the life-threatening SOST1 demonstrated by the teenagers who suffered blindness, deafness, and raised intracranial pressure, yet his congenital syndactyly was more striking by featuring bony fusion of digits. All three patients were from consanguineous families and heterozygosity for the SOST mutation was documented in the mothers of both teenagers. Thus, on the endogamous genetic background of Indian Tamils, SOST1 from sclerostin deficiency compared to SOST2 from LRP4 deactivation is a more severe and life-threatening disorder featuring complications due to osteosclerosis of especially the skull. In contrast, the syndactyly of SOST2 is particularly striking by involving bony fusion of some digits. Both the SOST and LRP4 mutations in this ethnic population likely reflect genetic founders.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2018 |
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| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:116 |
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| Enthalten in: |
Bone - 116(2018) vom: 05. Nov., Seite 321-332 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Whyte, Michael P [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 16.07.2019 Date Revised 09.12.2020 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bone.2018.07.022 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM287172856 |
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| 100 | 1 | |a Whyte, Michael P |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Sclerosteosis |b Report of type 1 or 2 in three Indian Tamil families and literature review |
| 264 | 1 | |c 2018 | |
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| 500 | |a Date Completed 16.07.2019 | ||
| 500 | |a Date Revised 09.12.2020 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2018 Elsevier Inc. All rights reserved. | ||
| 520 | |a Sclerosteosis (SOST) refers to two extremely rare yet similar skeletal dysplasias featuring a diffusely radiodense skeleton together with congenital syndactyly. SOST1 is transmitted as an autosomal recessive (AR) trait and to date caused by ten homozygous loss-of-function mutations within the gene SOST that encodes the inhibitor of Wnt-mediated bone formation, sclerostin. SOST2 is transmitted as an autosomal dominant (AD) or AR trait and to date caused by one heterozygous or two homozygous loss-of-function mutation(s), respectively, within the gene LRP4 that encodes the sclerostin interaction protein, low-density lipoprotein receptor-related protein 4 (LRP4). Herein, we investigated two teenagers and one middle-aged man with SOST in three families living in the state of Tamil Nadu in southern India. Next generation sequencing of their genomic DNA using our high bone density gene panel revealed SOST1 in the teenagers caused by a unique homozygous nonsense SOST mutation (c.129C > G, p.Tyr43X) and SOST2 in the man caused by homozygosity for one of the two known homozygous missense LRP4 mutations (c.3508C > T, p.Arg1170Trp). He becomes the fourth individual and the first non-European recognized with SOST2. His clinical course was milder than the life-threatening SOST1 demonstrated by the teenagers who suffered blindness, deafness, and raised intracranial pressure, yet his congenital syndactyly was more striking by featuring bony fusion of digits. All three patients were from consanguineous families and heterozygosity for the SOST mutation was documented in the mothers of both teenagers. Thus, on the endogamous genetic background of Indian Tamils, SOST1 from sclerostin deficiency compared to SOST2 from LRP4 deactivation is a more severe and life-threatening disorder featuring complications due to osteosclerosis of especially the skull. In contrast, the syndactyly of SOST2 is particularly striking by involving bony fusion of some digits. Both the SOST and LRP4 mutations in this ethnic population likely reflect genetic founders | ||
| 650 | 4 | |a Case Reports | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Blindness | |
| 650 | 4 | |a Consanguinity | |
| 650 | 4 | |a DXA | |
| 650 | 4 | |a Deafness | |
| 650 | 4 | |a Embryogenesis | |
| 650 | 4 | |a Hyperostosis | |
| 650 | 4 | |a Hyperphosphatasemia | |
| 650 | 4 | |a LRP4 | |
| 650 | 4 | |a Osteoblast | |
| 650 | 4 | |a Osteopetrosis | |
| 650 | 4 | |a Osteosclerosis | |
| 650 | 4 | |a SOST | |
| 650 | 4 | |a Sclerostin | |
| 650 | 4 | |a Syndactyly | |
| 650 | 4 | |a Wnt signaling | |
| 650 | 7 | |a Adaptor Proteins, Signal Transducing |2 NLM | |
| 650 | 7 | |a Bone Morphogenetic Proteins |2 NLM | |
| 650 | 7 | |a Genetic Markers |2 NLM | |
| 650 | 7 | |a LDL-Receptor Related Proteins |2 NLM | |
| 650 | 7 | |a LRP4 protein, human |2 NLM | |
| 650 | 7 | |a Minerals |2 NLM | |
| 650 | 7 | |a SOST protein, human |2 NLM | |
| 700 | 1 | |a Deepak Amalnath, S |e verfasserin |4 aut | |
| 700 | 1 | |a McAlister, William H |e verfasserin |4 aut | |
| 700 | 1 | |a Pedapati, Radhakrishna |e verfasserin |4 aut | |
| 700 | 1 | |a Muthupillai, Vivekanandan |e verfasserin |4 aut | |
| 700 | 1 | |a Duan, Shenghui |e verfasserin |4 aut | |
| 700 | 1 | |a Huskey, Margaret |e verfasserin |4 aut | |
| 700 | 1 | |a Bijanki, Vinieth N |e verfasserin |4 aut | |
| 700 | 1 | |a Mumm, Steven |e verfasserin |4 aut | |
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