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Mutation in ALOX12B likely cause of POI and also ichthyosis in a large Iranian pedigree

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Abstract

Premature ovarian insufficiency (POI) is a clinically and etiologically heterogeneous disorder characterized by menstrual irregularities and elevated levels of FSH before age of 40 years. Genetic anomalies are among the recognized causes of POI. Here, we aimed to identify the genetic cause of POI in an inbred pedigree with nine POI and two ichthyosis-affected members. Inheritance of POI and ichthyosis were, respectively, dominant and recessive. Reproduction-related information and measurements of relevant hormones were obtained. Genetic studies included homozygosity mapping, linkage analysis, exome sequencing, and screening of candidate variants. A mutation within ALOX12B, which is a known ichthyosis causing gene, was identified as cause of ichthyosis. ALOX12B encodes a protein involved in steroidogenesis and lipid metabolism. Considering the importance of steroidogenesis in reproduction functions, the possibility that the ALOX12B mutation is also cause of POI was considered. Screenings showed that the mutation segregated with POI status. Linkage analysis with respect to POI identified a single strongly linked locus (LOD > 3) that includes ALOX12B. Exome sequencing on POI-affected females identified the mutation in ALOX12B and also a sequence variation in SPNS2 within the linked locus. A possible contribution of the SPNS2 variation to POI was not strictly ruled out, but various data presented in the text including reported association of variations in related gene ALOX12 with menopause-age and role of ALOX12B in atretic bovine follicle formation argue in favor of ALOX12B. It is, therefore, concluded that the mutation in ALOX12B is the likely cause of POI in the pedigree.

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Abbreviations

POI:

Primary ovarian insufficiency

FSH:

Follicle stimulating hormone

StAR:

Steroidogenic acute regulatory protein

ALOX12B :

12(R)-Lipoxygenase (12R-LOX)

ARCI:

Autosomal recessive congenital ichthyosis

LH:

Luteinizing hormone

AMH:

Anti-Müllerian hormone

SNP:

Single-nucleotide polymorphisms

LOD:

Logarithm of the odds

NCIE:

Nonbullous congenital ichthyosiform erythroderma

PCR:

Polymerase chain reaction

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Acknowledgements

We would like to thank the patients and their family members for participating in the study, and we acknowledge the Iran National Science Foundation (INSF) and Iran's National Elites Foundation for funding the research. We also acknowledge Dr. PauliinaDamdimopoulou (Department of Clinical Science, Intervention and Technology, Karolinska Institute, Stockholm, Sweden) and Dr. JuhaKere (Department of Biosciences and Nutrition, Karolinska Institute and Center for Innovative Medicine, Stockholm, Sweden and Department of Medical Genetics, Haartman Institute and Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland) for discussions and for making possible for FD a tenure focused on reproductive biology at Karolinska Institute and for supervising her during the tenure.

Funding

This study was funded by the Iran National Science Foundation (INSF) (Grant No. 96008134) and by Iran’s National Elites Foundation.

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Authors and Affiliations

  1. Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran

    Afagh Alavi, Mohammad Masoud Rahimi Bidgoli & Davood Zare-Abdollahi

  2. School of Biology, University College of Science, University of Tehran, Tehran, Iran

    Faezeh Darki & Elahe Elahi

  3. Department of Gynecology and Obstetrics, Roointan Arash Women’s Health Research and Educational Hospital, Tehran University of Medical Sciences, Tehran, Iran

    Ashraf Moini

  4. Department of Dermatology, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran

    Mostafa M. Shahshahani

  5. Institute of Human Genetics, Medical Center—University of Freiburg, Freiburg, Germany

    Judith Fischer

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  1. Afagh Alavi
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  2. Faezeh Darki
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  3. Mohammad Masoud Rahimi Bidgoli
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  4. Davood Zare-Abdollahi
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  6. Mostafa M. Shahshahani
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  8. Elahe Elahi
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Contributions

AA: analysis of homozygosity mapping, SNP linkage, and exome sequencing data, mutation screening of ALOX12B in ichthyosis proband, ALOX12B segregation analysis pertaining to ichthyosis, contribution to design of research and writing of manuscript; FD: ALOX12B segregation analysis pertaining to POI, extensive literature search on ALOX12B; MMRB: SPNS2 segregation analysis pertaining to POI, DZA: karyotyping; AM: POI diagnosis; MMS: ichthyosis diagnosis; JF: mutation screening of ALOX12B and ALOXE3 in ichthyosis proband; EE: designed and supervised the research and wrote the manuscript.

Corresponding author

Correspondence to Elahe Elahi.

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Conflict of interest

Afagh Alavi, Faezeh Darki, Mohammad Masoud Rahimi Bidgoli, Davood Zare-Abdollahi, Ashraf Moini, Mostafa M Shahshahani, Judith Fischer, and Elahe Elahi declare that they have no conflict of interest.

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Informed consent was obtained from all individual participants included in the study.

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This research was performed with compliance with ethical standards. All procedures that involved human participants were performed in accordance with the ethical standards of the research committee of the University of Tehran and with compliance to the 1964 Helsinki declaration and its later amendments.

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Communicated by Stefan Hohmann.

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438_2020_1663_MOESM1_ESM.tif

Fig. S1 Normal karyotype of three POI affected females of pedigree IA-105. A. individual V-27; B. individual V-31; individual V-32. Supplementary file1 (TIF 844 kb)

438_2020_1663_MOESM2_ESM.pdf

Fig. S2 LOD plots of 22 autosomes pertaining to POI obtained under dominant model based on genotypes of eleven IA-105 members. It is evident that a locus on chromosome 17 achieves a LOD score > 3 and that no other region in the genome achieves a score > 1.5. Supplementary file2 (PDF 556 kb)

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Alavi, A., Darki, F., Bidgoli, M.M.R. et al. Mutation in ALOX12B likely cause of POI and also ichthyosis in a large Iranian pedigree. Mol Genet Genomics 295, 1039–1053 (2020). https://doi.org/10.1007/s00438-020-01663-z

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