Kidney Week

Abstract: FR-PO676

Pathogenic Mutations in Ras-MAPK Pathway Genes in Patients with Lupus Nephritis

Session Information

• Genetic Kidney Diseases: Cohort Studies - Genetic Associations and Diagnoses
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

• Zhang, Changming, National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

Changming Zhang

• Jing, Xiaoman, Southeast University School of Medicine, Nanjing, Jiangsu, China

Xiaoman Jing

• Zhang, Yangyang, National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

Yangyang Zhang, MD

• Jin, Ying, National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

Ying Jin, MD

• Liu, Zhihong, National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

Zhihong Liu, MD

Background

Pathogenic mutations in genes encoding components of Ras-MAPK pathway cause RASopathy, which include several clinically overlapping disorders, such as Noonan syndrome, Costello syndrome and neurofibromatosis. Here we describe five unrelated patients with lupus nephritis (LN) carrying mutations in components of Ras-MAPK pathway.

Methods

Causative mutations in the five LN patients were identified by whole-exome/genome sequencing and validated by Sanger sequencing.

Results

Five pathogenic mutations was identified in four Ras-MAPK genes, including NRAS:c.G38A: p.G13D; ARAF:c.C1435T: p.R479C; KRAS:c.T341C: p.V114A; PTPN11:c.G455A: p.R152H; NRAS:c.G34A: p.G12S. Three of them have been identified as pathogenic in individuals with Noonan syndrome and/or lupus. Two novel variants (R479C in ARAF and V114A in KRAS) are classified as likely pathogenic according to American College of Medical Genetics and Genomics criteria. The patients commonly manifested in early childhood and adolescence (range: 7-42 years of age). Kidney injury was the main feature, presenting with nephrotic syndrome (2/5), proteinuria and hematuria (2/5). Acute kidney injury and rapidly progressive nephritic syndrome was noted in one patient each. Other clinical features included mucocutaneous lesions (5/5), cardiac involvement (4/5, such as myocardial hypertrophy, pulmonary hypertension, enlargement of left atrium and ventricular), and arthralgia (3/5). Laboratory abnormalities included hypocomplementemia (5/5), presence of antiphospholipid (4/5), decreased Treg cells (3/3 patients tested), pancytopenia (3/5, one consistent with Evans syndrome), and persistent monocytosis (two with NRAS mutations). Histopathological findings included LN-V in two, LN-IV+V and LN-III+V in one patient each. All patients received methylprednisolone pulse therapy, followed by prednisone combined with cyclophosphamide or mycophenolate mofetil or tacrolimus. The patient with NRAS p.G12S mutation also received Rituximab therapy. Most patients responded well, with the exception of the patient with NRAS p.G13D mutation who died.

Conclusion

Kidney involvement may be the main feature of the clinical spectrum of RASopathy. Genetic screening should be considered for early-onset LN patients.

Funding

• Government Support – Non-U.S.