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Revealing the functions of novel mutations in RAB3GAP1 in Martsolf and Warburg micro syndromes.
Am J Med Genet A. 2019 04; 179(4):579-587.AJ

Abstract

PURPOSE

Martsolf (MS) and Warburg micro syndromes (WARBM) are rare autosomal recessive inherited allelic disorders, which share similar clinical features including microcephaly, intellectual disability, brain malformations, ocular abnormalities, and spasticity. Here, we revealed the functions of novel mutations in RAB3GAP1 in a Turkish female patient with MS and two siblings with WARBM. We also present a review of MS patients as well as all reported RAB3GAP1 pathogenic mutations in the literature.

METHODS

We present a female with MS phenotype and two siblings with WARBM having more severe phenotypes. We utilized whole-exome sequencing to identify the molecular basis of these syndromes and confirmed suspected variants by Sanger sequencing. Quantitative (q) RT-PCR analysis was carried out to reveal the functions of novel splice site mutation detected in MS patient.

RESULTS

We found a novel homozygous c.2607-1G>C splice site mutation in intron 22 of RAB3GAP1 in MS patient and a novel homozygous c.2187_2188delinsCT, p.(Met729_Lys730delinsIleTer) mutation in exon 19 of RAB3GAP1 in the WARBM patients. We showed exon skipping in MS patient by Sanger sequencing and gel electrophoresis. qRT-PCR analysis demonstrated the reduced expression of RAB3GAP1 in the patient with the c.2607-1G>C splice site mutation compared to a healthy control individual.

CONCLUSION

Here, we have studied two novel RAB3GAP1 mutations in two different phenotypes; a MS associated novel splice site mutation, and a WARBM1 associated novel deletion-insertion mutation. Our findings suggest that this splice site mutation is responsible for milder phenotype and the deletion-insertion mutation presented here is associated with severe phenotype.

Authors+Show Affiliations

Department of Internal Medicine, Division of Medical Genetics, Istanbul University, Istanbul, Turkey.Molecular Biology and Genetics Department, Erzurum Technical University, Erzurum, Turkey.Department of Medical Genetics, Istanbul University, Cerrahpasa Medical School, Istanbul, Turkey.Department of Internal Medicine, Division of Medical Genetics, Istanbul University, Istanbul, Turkey.Advanced Genomics and Bioinformatics Research Center, The Scientific and Technological Research Council of Turkey (TUBITAK-BILGEM), Kocaeli, Turkey.Advanced Genomics and Bioinformatics Research Center, The Scientific and Technological Research Council of Turkey (TUBITAK-BILGEM), Kocaeli, Turkey.Department of Medical Genetics, Istanbul University, Cerrahpasa Medical School, Istanbul, Turkey. Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas.

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30730599

Citation

Koparir, Asuman, et al. "Revealing the Functions of Novel Mutations in RAB3GAP1 in Martsolf and Warburg Micro Syndromes." American Journal of Medical Genetics. Part A, vol. 179, no. 4, 2019, pp. 579-587.
Koparir A, Karatas OF, Yilmaz SS, et al. Revealing the functions of novel mutations in RAB3GAP1 in Martsolf and Warburg micro syndromes. Am J Med Genet A. 2019;179(4):579-587.
Koparir, A., Karatas, O. F., Yilmaz, S. S., Suer, I., Ozer, B., Yuceturk, B., & Ozen, M. (2019). Revealing the functions of novel mutations in RAB3GAP1 in Martsolf and Warburg micro syndromes. American Journal of Medical Genetics. Part A, 179(4), 579-587. https://doi.org/10.1002/ajmg.a.61065
Koparir A, et al. Revealing the Functions of Novel Mutations in RAB3GAP1 in Martsolf and Warburg Micro Syndromes. Am J Med Genet A. 2019;179(4):579-587. PubMed PMID: 30730599.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Revealing the functions of novel mutations in RAB3GAP1 in Martsolf and Warburg micro syndromes. AU - Koparir,Asuman, AU - Karatas,Omer Faruk, AU - Yilmaz,Seda Salman, AU - Suer,Ilknur, AU - Ozer,Bugra, AU - Yuceturk,Betul, AU - Ozen,Mustafa, Y1 - 2019/02/07/ PY - 2018/09/27/received PY - 2019/01/17/revised PY - 2019/01/17/accepted PY - 2019/2/8/pubmed PY - 2020/4/23/medline PY - 2019/2/8/entrez KW - RAB3GAP1 KW - Martsolf syndrome KW - Warburg micro syndromes KW - whole-exome sequencing, splice site mutation SP - 579 EP - 587 JF - American journal of medical genetics. Part A JO - Am J Med Genet A VL - 179 IS - 4 N2 - PURPOSE: Martsolf (MS) and Warburg micro syndromes (WARBM) are rare autosomal recessive inherited allelic disorders, which share similar clinical features including microcephaly, intellectual disability, brain malformations, ocular abnormalities, and spasticity. Here, we revealed the functions of novel mutations in RAB3GAP1 in a Turkish female patient with MS and two siblings with WARBM. We also present a review of MS patients as well as all reported RAB3GAP1 pathogenic mutations in the literature. METHODS: We present a female with MS phenotype and two siblings with WARBM having more severe phenotypes. We utilized whole-exome sequencing to identify the molecular basis of these syndromes and confirmed suspected variants by Sanger sequencing. Quantitative (q) RT-PCR analysis was carried out to reveal the functions of novel splice site mutation detected in MS patient. RESULTS: We found a novel homozygous c.2607-1G>C splice site mutation in intron 22 of RAB3GAP1 in MS patient and a novel homozygous c.2187_2188delinsCT, p.(Met729_Lys730delinsIleTer) mutation in exon 19 of RAB3GAP1 in the WARBM patients. We showed exon skipping in MS patient by Sanger sequencing and gel electrophoresis. qRT-PCR analysis demonstrated the reduced expression of RAB3GAP1 in the patient with the c.2607-1G>C splice site mutation compared to a healthy control individual. CONCLUSION: Here, we have studied two novel RAB3GAP1 mutations in two different phenotypes; a MS associated novel splice site mutation, and a WARBM1 associated novel deletion-insertion mutation. Our findings suggest that this splice site mutation is responsible for milder phenotype and the deletion-insertion mutation presented here is associated with severe phenotype. SN - 1552-4833 UR - https://www.unboundmedicine.com/medline/citation/30730599/Revealing_the_functions_of_novel_mutations_in_RAB3GAP1_in_Martsolf_and_Warburg_micro_syndromes_ L2 - https://doi.org/10.1002/ajmg.a.61065 DB - PRIME DP - Unbound Medicine ER -