{
  "abstract": "Introduction Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes. MODY type 9 (MODY9) is a rare subtype caused by variants in the PAX4 gene. However, the pathogenicity and mechanisms of many PAX4 variants remain unclear. This study aimed to evaluate the clinical relevance and pathogenic mechanisms of three novel PAX4 variants identified in patients with suspected MODY.Research design and methods Three unrelated patients with early-onset diabetes and a family history of the disease were screened for PAX4 variants using whole-exome and Sanger sequencing. In silico predictions, evolutionary conservation analysis, and structural modeling were performed. Functional studies were conducted in MIN6 cells to assess protein expression, subcellular localization, and degradation pathways.Results Three novel PAX4 variants (c.83delA; p.Gln28ArgfsTer6, c.35T>C; p.Leu12Pro, and c.488G>C; p.Arg163Pro) were identified. Expression of p.Gln28ArgfsTer6 was undetectable, likely due to nonsense-mediated decay. In contrast, p.Leu12Pro and p.Arg163Pro retained nuclear localization but resulted in markedly reduced protein levels. Treatment with the proteasome inhibitor MG132 restored protein levels of the missense mutants, indicating enhanced proteasomal degradation as the likely mechanism. These findings suggest that certain PAX4 variants impair β-cell function by destabilizing the protein post-translationally.Conclusions This study expands the spectrum of PAX4 variants and provides novel mechanistic insights into the pathogenesis of MODY9. Our results highlight the importance of assessing protein-level consequences for variant interpretation and support the integration of functional assays into MODY genetic diagnostic workflows.",
  "authors": [
    {
      "affiliations": [
        "Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education",
        "Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China",
        "Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education",
        "Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China",
        "Shandong Key Laboratory of Endocrine Metabolism and Aging, Jinan, Shandong, China",
        "Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China",
        "“Chuangxin China” Innovation Base of stem cell and Gene Therapy for endocrine Metabolic diseases, Jinan, Shandong, China",
        "Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China",
        "Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China"
      ],
      "name": "Xinyu Chen"
    },
    {
      "affiliations": [
        "Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education",
        "Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China",
        "Shandong Key Laboratory of Endocrine Metabolism and Aging, Jinan, Shandong, China",
        "Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China",
        "“Chuangxin China” Innovation Base of stem cell and Gene Therapy for endocrine Metabolic diseases, Jinan, Shandong, China",
        "Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China",
        "Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China"
      ],
      "name": "Yang Tian"
    },
    {
      "affiliations": [
        "Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education",
        "Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China",
        "Shandong Key Laboratory of Endocrine Metabolism and Aging, Jinan, Shandong, China",
        "Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China",
        "“Chuangxin China” Innovation Base of stem cell and Gene Therapy for endocrine Metabolic diseases, Jinan, Shandong, China",
        "Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China",
        "Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China"
      ],
      "name": "Wanhong Wu"
    },
    {
      "affiliations": [
        "Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education",
        "Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China",
        "Shandong Key Laboratory of Endocrine Metabolism and Aging, Jinan, Shandong, China",
        "Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China",
        "“Chuangxin China” Innovation Base of stem cell and Gene Therapy for endocrine Metabolic diseases, Jinan, Shandong, China",
        "Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China",
        "Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China"
      ],
      "name": "Luna Liu"
    },
    {
      "affiliations": [
        "Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education",
        "Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China",
        "Shandong Key Laboratory of Endocrine Metabolism and Aging, Jinan, Shandong, China",
        "Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China",
        "“Chuangxin China” Innovation Base of stem cell and Gene Therapy for endocrine Metabolic diseases, Jinan, Shandong, China",
        "Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China",
        "Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China"
      ],
      "name": "Huixiao Wu"
    },
    {
      "affiliations": [
        "Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education",
        "Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China",
        "Shandong Key Laboratory of Endocrine Metabolism and Aging, Jinan, Shandong, China",
        "Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China",
        "“Chuangxin China” Innovation Base of stem cell and Gene Therapy for endocrine Metabolic diseases, Jinan, Shandong, China",
        "Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China",
        "Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China"
      ],
      "name": "Yidan Zhang"
    },
    {
      "affiliations": [
        "Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China"
      ],
      "name": "Ning Suo"
    },
    {
      "affiliations": [
        "Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education",
        "Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China",
        "Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education",
        "Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China",
        "Shandong Key Laboratory of Endocrine Metabolism and Aging, Jinan, Shandong, China",
        "Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, China",
        "“Chuangxin China” Innovation Base of stem cell and Gene Therapy for endocrine Metabolic diseases, Jinan, Shandong, China",
        "Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, China",
        "Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, China"
      ],
      "name": "Chao Xu"
    }
  ],
  "title": "Identification and characterization of novel PAX4 variants in patients with suspected MODY9",
  "uid": "119e2426-517d-599f-8af2-f588003f44d1"
}