A RARE INHERITED CASE OF MYH9-RELATED NEPHROPATHY WITHOUT THROMBOCYTOPENIA INVOLVING AN EXON 20 MUTATION

MYH9-related disease (MYH9-RD) is an inherited disorder characterized by congenital macrothrombocytopenia, nephropathy, and sensorineural hearing loss. Most MYH9-RD patients present with thrombocytopenia, and 30%–70% develop renal involvement. These patients often progress to chronic kidney disease in their 20s and end-stage kidney disease in their 40s. MYH9-RD is caused by mutations in the MYH9 gene, which encodes the heavy chain of non-muscle myosin IIA (NMMHC-ⅡA). NMMHC-IIA is an actin-binding protein that plays a significant role in cell adhesion and maintenance of tissue architecture. Macrothrombocytopenia in MYH9-RD is associated with the defects of the late events of platelet biogenesis, that is, the release of platelets from the proplatelet free ends. The impairment of the contractile force generated by the actomyosin cytoskeleton, which separates platelets from the free ends of proplatelets and limits platelet size, causing the defect of proplatelet branching. Additionally, impaired function of a glomerular filtration barrier caused by the abnormal distribution of myosin IIA in podocytes is considered a potential cause of renal involvement in MYH9-RD. MYH9-RD cases without thrombocytopenia are extremely rare.

A 17-year-old female patient was referred to our clinic for proteinuria and microscopic hematuria. She was diagnosed with hearing loss at the age of 6 years and was under the care of the otolaryngology department. She was diagnosed with functional hearing loss at the age of 9 years. Urinalysis performed at the age of 15 years during a routine health checkup revealed proteinuria and hematuria. Laboratory findings were as follows: platelet count: 200 × 109/L (no thrombocytopenia); urinary protein-to-creatinine ratio (UP/UCr), 0.3 g/gCr; hematuria with 50–99 red blood cells/high-power field; and serum creatinine, 0.52 mg/dL. She showed a gradual increase in proteinuria, with UP/UCr reaching 1.3 g/gCr. 

Due to hearing loss and a family history (grandmother had suffered from renal failure and aunt had proteinuria), genetic testing was performed using whole-exome sequencing with a next-generation sequencer. Results revealed a heterozygous missense mutation in exon 20 of the MYH9 gene, which resulted in an amino acid substitution of tryptophan to arginine at codon 802. At the age of 17 years, a kidney biopsy revealed minimal glomerular changes on light microscopy, without significant immunofluorescence findings; however, mesangial expansion and foot process effacement/detachment on electron microscopy were consistent with MYH9-RD.

In the present case, the MYH9 mutation identified in exon 20, which affects the neck domain, was unusual. Moreover, MYH9-RD without thrombocytopenia is extremely rare. Patients with MYH9 mutations affecting the head domain present with more severe thrombocytopenia and larger platelets compared to patients harboring mutations impacting the tail domain. The phenotypic characteristics of patients with MYH9 mutations impacting the neck domain have not been well established; however, in the present case, careful long-term monitoring of renal function was necessary, considering the symptoms resembling Alport syndrome and progressive proteinuria.