Kidney Week

Abstract: TH-PO0139

Sibling Cases of Isolated Asymptomatic Proteinuria Without Megaloblastic Anemia Caused by Novel Homozygous AMN Variants

Session Information

• Integrative Genomics and Multi-Omics in Noncystic Genetic Kidney Disease
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Non-Cystic (Complex and Non-Cystic Monogenic)

Authors

• Ando, Taro, Tokyo Joshi Ika Daigaku, Shinjuku, Tokyo, Japan

Taro Ando, MD

• Shirai, Yoko, Tokyo Joshi Ika Daigaku, Shinjuku, Tokyo, Japan

Yoko Shirai, MD, PhD

• Nakatani, Ryo, Tokyo Joshi Ika Daigaku, Shinjuku, Tokyo, Japan

Ryo Nakatani, MD

• Eguchi, Makoto, Yamagata Daigaku, Yamagata, Yamagata Prefecture, Japan

Makoto Eguchi, DrMed

• Hashimoto, Taeko, Tokyo Joshi Ika Daigaku, Shinjuku, Tokyo, Japan

Taeko Hashimoto, MD

• Harita, Yutaka, Tokyo Daigaku, Bunkyo, Tokyo, Japan

Yutaka Harita, MD, PhD

• Yamamoto, Toshiyuki, Tokyo Joshi Ika Daigaku, Shinjuku, Tokyo, Japan

Toshiyuki Yamamoto, MD

• Miura, Kenichiro, Tokyo Joshi Ika Daigaku, Shinjuku, Tokyo, Japan

Kenichiro Miura, MD, PhD

Introduction

AMN encodes amnionless, a component of the cubam receptor complex involved in intestinal vitamin B12 absorption and proximal tubular protein reabsorption. Biallelic AMN variants cause Imerslund-Gräsbeck syndrome type 2, typically characterized by megaloblastic anemia and low-molecular-weight proteinuria. Isolated asymptomatic proteinuria without megaloblastic anemia has been reported in only one prior case, and AMN is not routinely included in genetic testing panels for unexplained proteinuria.

Case Description

We report two Japanese brothers, aged 12 and 8 years, with persistent asymptomatic proteinuria detected by urinary screening. Their urinary protein/creatinine ratios were 0.6–0.8 and 0.4–0.5 g/gCr, respectively. Neither had hematuria, edema, anemia, or extrarenal manifestations, and kidney function was preserved. Both had reduced serum vitamin B12 levels, at 131 and 79 pg/mL, despite the absence of megaloblastic anemia. Urinary alpha-1-microglobulin was mildly elevated in the elder brother but normal in the younger brother. Kidney biopsy was not performed because the family declined the procedure.
Whole-exome sequencing identified a novel homozygous AMN variant, NM_030943.4:c.750T>G, p.Cys250Trp, in both siblings. Both unaffected parents were heterozygous for the variant, consistent with segregation in the family. The variant was extremely rare in population databases and had no previous reports. Multiple in silico tools predicted deleterious effects. Protein structural analysis using Missense3D based on AlphaFold DB predicted disruption of the Cys250–Cys234 disulfide bond and a buried-to-exposed conformational shift. These structural changes were consistent with a deleterious effect on amnionless protein stability. The variant was classified as Likely Pathogenic based on ACMG/AMP criteria with ClinGen recommendations.

Discussion

This sibling pair suggests that AMN-associated disease can present as persistent asymptomatic proteinuria with subclinical vitamin B12 deficiency but without megaloblastic anemia. These findings support including AMN in genetic testing panels for children with isolated asymptomatic proteinuria.