Genetic analysis of the <i>ALMS1</i> gene in two families affected with Alström syndrome_Chinese Journal of Ocular Fundus Diseases

Authors：

Zhou Zhongqiang ¹ , Wei Yuanmeng ¹ , Tang He ¹ ,  Peng Haiying ¹ , Shi Pingling ¹ , Li Guanfeng ² , Li Miao ¹

1. Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou 450003, China;
2. Department of Opthalmology, Henan Children's Hospital, Children's Hospital Affiliated of Zhengzhou University, Henan Provincial Key Laboratory of Children's Genetic and Metabolic Diseases, Zhengzhou 450018, China;

Corresponding author：

Peng Haiying, Email: angelphy@163.com

Keywords：

Alström syndrome; ALMS1 gene; New mutation

DOI：

10.3760/cma.j.cn511434-20230222-00136

Video：

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Objective To identify two pathogenic gene mutations in two families with Alström syndrome (ALMS). Methods A retrospective clinical study. Two patients and five family members from two Han families of ALMS diagnosed at Henan Eye Hospital from August 2020 to December 2021 were enrolled in this study. All participants underwent comprehensive ophthalmic examinations including best corrected visual acuity (BCVA), color test, slit-lamp, fundus biomicroscopy with slit lamp, fundus color photography, optical coherence tomography (OCT) and full-field electroretinography (ff-ERG) after the detailed history of the patient was taken. Five millilitres peripheral venous blood of each subject was collected, and the whole genome DNA was extracted. The pathogenic genes and mutation sites were identified using whole exome sequencing and the identified mutations were verified by Sanger sequencing. Mutation sites were analyzed via bioinformatics softwares. Results Family one included one victim and two members and family two included one victim and three members. Proband in the first family was a four-year old boy whose chief complaint was poor vision along with photophobia since born, while proband in the second family was a 12-year old girl whose chief complaint was the same. The boy proband could not distinguish color, and both the anterior segment and fundus were normal. Ellipsoid zone of the boy was unclear in both eyes in OCT, and though rod system function decreased mildly-moderately in both eyes, the cone system function decreased severely in ff-ERG. The girl could not distinguish color as well, and the anterior segment was normal, though obvious pigmentary change could be seen in both retinas. The integrity of outer retinal bands was unclear in both eyes in OCT, and both cone and rod systems function decreased severely in both eyes in ff-ERG. Gene tests and bioinformatics analyze showed c.468dupT and c.10819C>T of ALMS1 gene in family one were novel mutations and c.10819C>T in family one and c.10831_10832del in family two were pathogenic mutations. Conclusions M1, M2 and M3, M4 may be pathogenic gene variants in family 1 and family 2, respectively. The compound heterozygous mutation, c.468dupT and c.10819C>T of ALMS1 gene was a novel mutation.

Citation： Zhou Zhongqiang, Wei Yuanmeng, Tang He, Peng Haiying, Shi Pingling, Li Guanfeng, Li Miao. Genetic analysis of the ALMS1 gene in two families affected with Alström syndrome. Chinese Journal of Ocular Fundus Diseases, 2023, 39(7): 538-543. doi: 10.3760/cma.j.cn511434-20230222-00136 Copy

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2.	Hearn TALMS1 and Alström syndrome: a recessive form of metabolic, neurosensory and cardiac deficits[J]. J Mol Med (Berl)2019971117. DOI:10.1007/s00109-018-1714-x.
3.	Richards S, Aziz N, Bale S, et alStandards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med2015175405424. DOI:10.1038/gim.2015.30.
4.	Choudhury AR, Munonye I, Sanu KP, et alA review of Alström syndrome: a rare monogenic ciliopathy[J]. Intractable Rare Dis Res2021104257262. DOI:10.5582/irdr.2021.01113.
5.	Cheng WY, Ma MJ, Yuan SQ, et alNew pathogenic variants of ALMS1 gene in two Chinese families with Alström syndrome[J]. BMC Ophthalmol2022, 26, 22(1): 386. DOI:10.1186/s12886-022-02597-3.
6.	丁宇, 张倩文, 贺影忠, 等七例Alström综合征的ALMS1基因变异分析[J]. 中华医学遗传学杂志2021382112116. DOI: 10.3760/cma.j.cn511374-20200115-00033..Ding Y, Zhang QW, He YZ, et alAnalysis of ALMS1 gene variants in seven patients with Alström syndrome[J]. Chin J Med Genet2021382112116. DOI: 10.3760/cma.j.cn511374-20200115-00033.
7.	魏莹, 刘戈力, 郑荣秀, 等Alstrom综合征1例报告及文献复习[J]. 天津医科大学学报2020266572574. DOI:10.3760/cma.j.cmcr.2022.e04865..Wei Y, Liu GL, Zheng RX, et alAlström syndrome, report of a case and literature review[J]. Journal of Tianjin Medical University2020266572574. DOI:10.3760/cma.j.cmcr.2022.e04865.
8.	王云芳, 万小艳, 牛瑞兰, 等Alstrom综合征两例报道[J]. 中国糖尿病杂志2023312139144. DOI: 10.3969/j.issn.1006-6187.2023.02.012..Wang YF, Wan XY, Niu RL, et alAlstrom syndrome: two cases report[J]. Chin J Diabetes2023312139144. DOI: 10.3969/j.issn.1006-6187.2023.02.012.
9.	杨慧杰, 李德, 白卉泠, 等一例ALMS1基因复合杂合突变所致的Alstrom综合征的诊疗和基因检测分析[J]. 遗传2022441211481157. DOI: 10.16288/j.yczz.22-217..Yang HJ, Li D, Bai HL, et alDiagnosis, treatment and genetic analysis of a case of Alstrom syndrome caused by compoud heterozygous mutation of ALMS1[J]. Hereditas (Beijing)2022441211481157. DOI: 10.16288/j.yczz.22-217.
10.	刘晶晶, 龚方戚儿童Alstrom综合征1例报告及文献复习[J]. 温州医科大学学报2021512163-165, 169. DOI: 10.3969/j.issn.2095-9400.2021.02.017..Liu JJ, Gong FQAlström syndrome, report of a pediatric case and literature review[J]. Journal of Wenzhou Medical University2021512163-165, 169. DOI: 10.3969/j.issn.2095-9400.2021.02.017.
11.	韦宝玲, 任毅, 杨静Alstrom综合征[J]. 临床荟萃2018339813817. DOI: 10.3969/j.issn.1004-583X.2018.09.017..Wei BL, Ren Y, Yang JAlström syndrome[J]. Clinical Focus2018339813817. DOI: 10.3969/j.issn.1004-583X.2018.09.017.
12.	王秋菊, 沈亦平, 邬玲仟, 等遗传变异分类标准与指南[J]. 中国科学: 生命科学2017476668688. DOI: 10.1360/N052017-00099.Wang QJ, Shen YP, Wu LQ, et alStandards and guidelines for the interpretation of sequence variants[J]. Scientia Sinica Vitae (Zhongguo Kexue Shengming Kexue)2017476668688. DOI: 10.1360/N052017-00099.
13.	彭晓燕. 问诊——眼病相关的症状和病史的分析[M]//彭晓燕. 眼底病诊断思辨. 北京: 人民卫生出版社, 2009: 21..Peng XY. Consultation: an analysis of the symptoms and history associated with eye disease[M]//Peng XY. Ocular fundus diseases evaluation and diagnosis. Beijing: People’s Medical Publishing House, 2009: 21.
14.	Waldman M, Han JC, Reyes-Capo DP, et alAlstrom syndrome: renal findings in correlation with obesity, insulin resistance, dyslipidemia and cardiomyopathy in 38 patients prospectively evaluated at the NIH clinical center[J]. Mol Genet Metab20181251-2181191. DOI:10.1016/j.ymgme.2018.07.010.
15.	Collin GB, Marshall JD, King BL, et al. The Alström syndrome protein, ALMS1, interacts with α-actinin and components of the endosome recycling pathway[J/OL]. PLoS One, 2012, 7(5): e37925[2012-05-31]. https://europepmc.org/article/MED/22693585. DOI:10.1371/journal.pone.0037925.
16.	Zhou BH, Lin WL, Long YL, et alNotch signaling pathway: architecture, disease, and therapeutics[J]. Signal Transduct Target Ther20227195. DOI:10.1038/s41392-022-00934-y.

1. Dassie F, Favaretto F, Bettini S, et alAlström syndrome: an ultra-rare monogenic disorder as a model for insulin resistance, type 2 diabetes mellitus and obesity[J]. Endocrine2021713618625. DOI:10.1007/s12020-021-02643-y.
2. Hearn TALMS1 and Alström syndrome: a recessive form of metabolic, neurosensory and cardiac deficits[J]. J Mol Med (Berl)2019971117. DOI:10.1007/s00109-018-1714-x.
3. Richards S, Aziz N, Bale S, et alStandards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med2015175405424. DOI:10.1038/gim.2015.30.
4. Choudhury AR, Munonye I, Sanu KP, et alA review of Alström syndrome: a rare monogenic ciliopathy[J]. Intractable Rare Dis Res2021104257262. DOI:10.5582/irdr.2021.01113.
5. Cheng WY, Ma MJ, Yuan SQ, et alNew pathogenic variants of ALMS1 gene in two Chinese families with Alström syndrome[J]. BMC Ophthalmol2022, 26, 22(1): 386. DOI:10.1186/s12886-022-02597-3.
6. 丁宇, 张倩文, 贺影忠, 等七例Alström综合征的ALMS1基因变异分析[J]. 中华医学遗传学杂志2021382112116. DOI: 10.3760/cma.j.cn511374-20200115-00033..Ding Y, Zhang QW, He YZ, et alAnalysis of ALMS1 gene variants in seven patients with Alström syndrome[J]. Chin J Med Genet2021382112116. DOI: 10.3760/cma.j.cn511374-20200115-00033.
7. 魏莹, 刘戈力, 郑荣秀, 等Alstrom综合征1例报告及文献复习[J]. 天津医科大学学报2020266572574. DOI:10.3760/cma.j.cmcr.2022.e04865..Wei Y, Liu GL, Zheng RX, et alAlström syndrome, report of a case and literature review[J]. Journal of Tianjin Medical University2020266572574. DOI:10.3760/cma.j.cmcr.2022.e04865.
8. 王云芳, 万小艳, 牛瑞兰, 等Alstrom综合征两例报道[J]. 中国糖尿病杂志2023312139144. DOI: 10.3969/j.issn.1006-6187.2023.02.012..Wang YF, Wan XY, Niu RL, et alAlstrom syndrome: two cases report[J]. Chin J Diabetes2023312139144. DOI: 10.3969/j.issn.1006-6187.2023.02.012.
9. 杨慧杰, 李德, 白卉泠, 等一例ALMS1基因复合杂合突变所致的Alstrom综合征的诊疗和基因检测分析[J]. 遗传2022441211481157. DOI: 10.16288/j.yczz.22-217..Yang HJ, Li D, Bai HL, et alDiagnosis, treatment and genetic analysis of a case of Alstrom syndrome caused by compoud heterozygous mutation of ALMS1[J]. Hereditas (Beijing)2022441211481157. DOI: 10.16288/j.yczz.22-217.
10. 刘晶晶, 龚方戚儿童Alstrom综合征1例报告及文献复习[J]. 温州医科大学学报2021512163-165, 169. DOI: 10.3969/j.issn.2095-9400.2021.02.017..Liu JJ, Gong FQAlström syndrome, report of a pediatric case and literature review[J]. Journal of Wenzhou Medical University2021512163-165, 169. DOI: 10.3969/j.issn.2095-9400.2021.02.017.
11. 韦宝玲, 任毅, 杨静Alstrom综合征[J]. 临床荟萃2018339813817. DOI: 10.3969/j.issn.1004-583X.2018.09.017..Wei BL, Ren Y, Yang JAlström syndrome[J]. Clinical Focus2018339813817. DOI: 10.3969/j.issn.1004-583X.2018.09.017.
12. 王秋菊, 沈亦平, 邬玲仟, 等遗传变异分类标准与指南[J]. 中国科学: 生命科学2017476668688. DOI: 10.1360/N052017-00099.Wang QJ, Shen YP, Wu LQ, et alStandards and guidelines for the interpretation of sequence variants[J]. Scientia Sinica Vitae (Zhongguo Kexue Shengming Kexue)2017476668688. DOI: 10.1360/N052017-00099.
13. 彭晓燕. 问诊——眼病相关的症状和病史的分析[M]//彭晓燕. 眼底病诊断思辨. 北京: 人民卫生出版社, 2009: 21..Peng XY. Consultation: an analysis of the symptoms and history associated with eye disease[M]//Peng XY. Ocular fundus diseases evaluation and diagnosis. Beijing: People’s Medical Publishing House, 2009: 21.
14. Waldman M, Han JC, Reyes-Capo DP, et alAlstrom syndrome: renal findings in correlation with obesity, insulin resistance, dyslipidemia and cardiomyopathy in 38 patients prospectively evaluated at the NIH clinical center[J]. Mol Genet Metab20181251-2181191. DOI:10.1016/j.ymgme.2018.07.010.
15. Collin GB, Marshall JD, King BL, et al. The Alström syndrome protein, ALMS1, interacts with α-actinin and components of the endosome recycling pathway[J/OL]. PLoS One, 2012, 7(5): e37925[2012-05-31]. https://europepmc.org/article/MED/22693585. DOI:10.1371/journal.pone.0037925.
16. Zhou BH, Lin WL, Long YL, et alNotch signaling pathway: architecture, disease, and therapeutics[J]. Signal Transduct Target Ther20227195. DOI:10.1038/s41392-022-00934-y.

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Genetic analysis of the ALMS1 gene in two families affected with Alström syndrome

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