Biallelic GALM pathogenic variants cause a novel type of galactosemia

Yoichi Wada, Atsuo Kikuchi, Natsuko Arai-Ichinoi, Osamu Sakamoto, Yusuke Takezawa, Shinya Iwasawa, Tetsuya Niihori, Hiromi Nyuzuki, Yoko Nakajima, Erika Ogawa, Mika Ishige, Hiroki Hirai, Hideo Sasai, Ryoji Fujiki, Matsuyuki Shirota, Ryo Funayama, Masayuki Yamamoto, Tetsuya Ito, Osamu Ohara, Keiko NakayamaYoko Aoki, Seizo Koshiba, Toshiyuki Fukao, Shigeo Kure

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Purpose: Galactosemia is caused by metabolic disturbances at various stages of galactose metabolism, including deficiencies in enzymes involved in the Leloir pathway (GALT, GALK1, and GALE). Nevertheless, the etiology of galactosemia has not been identified in a subset of patients. This study aimed to explore the causes of unexplained galactosemia. Methods: Trio-based exome sequencing and/or Sanger sequencing was performed in eight patients with unexplained congenital galactosemia. In vitro enzymatic assays and immunoblot assays were performed to confirm the pathogenicity of the variants. Results: The highest blood galactose levels observed in each patient were 17.3–41.9 mg/dl. Bilateral cataracts were observed in two patients. In all eight patients, we identified biallelic variants (p.Arg82*, p.Ile99Leufs*46, p.Gly142Arg, p.Arg267Gly, and p.Trp311*) in the GALM encoding galactose mutarotase, which catalyzes epimerization between β- and α-D-galactose in the first step of the Leloir pathway. GALM enzyme activities were undetectable in lymphoblastoid cell lines established from two patients. Immunoblot analysis showed the absence of the GALM protein in the patients’ peripheral blood mononuclear cells. In vitro GALM expression and protein stability assays revealed altered stabilities of the variant GALM proteins. Conclusion: Biallelic GALM pathogenic variants cause galactosemia, suggesting the existence of type IV galactosemia.

Original languageEnglish
Pages (from-to)1286-1294
Number of pages9
JournalGenetics in Medicine
Volume21
Issue number6
DOIs
Publication statusPublished - 01-06-2019

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Galactosemias
Galactose
Exome
Protein Stability
Enzyme Assays
Enzymes
Cataract
Virulence
Blood Cells
Proteins
Cell Line

All Science Journal Classification (ASJC) codes

  • Genetics(clinical)

Cite this

Wada, Y., Kikuchi, A., Arai-Ichinoi, N., Sakamoto, O., Takezawa, Y., Iwasawa, S., ... Kure, S. (2019). Biallelic GALM pathogenic variants cause a novel type of galactosemia. Genetics in Medicine, 21(6), 1286-1294. https://doi.org/10.1038/s41436-018-0340-x
Wada, Yoichi ; Kikuchi, Atsuo ; Arai-Ichinoi, Natsuko ; Sakamoto, Osamu ; Takezawa, Yusuke ; Iwasawa, Shinya ; Niihori, Tetsuya ; Nyuzuki, Hiromi ; Nakajima, Yoko ; Ogawa, Erika ; Ishige, Mika ; Hirai, Hiroki ; Sasai, Hideo ; Fujiki, Ryoji ; Shirota, Matsuyuki ; Funayama, Ryo ; Yamamoto, Masayuki ; Ito, Tetsuya ; Ohara, Osamu ; Nakayama, Keiko ; Aoki, Yoko ; Koshiba, Seizo ; Fukao, Toshiyuki ; Kure, Shigeo. / Biallelic GALM pathogenic variants cause a novel type of galactosemia. In: Genetics in Medicine. 2019 ; Vol. 21, No. 6. pp. 1286-1294.
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abstract = "Purpose: Galactosemia is caused by metabolic disturbances at various stages of galactose metabolism, including deficiencies in enzymes involved in the Leloir pathway (GALT, GALK1, and GALE). Nevertheless, the etiology of galactosemia has not been identified in a subset of patients. This study aimed to explore the causes of unexplained galactosemia. Methods: Trio-based exome sequencing and/or Sanger sequencing was performed in eight patients with unexplained congenital galactosemia. In vitro enzymatic assays and immunoblot assays were performed to confirm the pathogenicity of the variants. Results: The highest blood galactose levels observed in each patient were 17.3–41.9 mg/dl. Bilateral cataracts were observed in two patients. In all eight patients, we identified biallelic variants (p.Arg82*, p.Ile99Leufs*46, p.Gly142Arg, p.Arg267Gly, and p.Trp311*) in the GALM encoding galactose mutarotase, which catalyzes epimerization between β- and α-D-galactose in the first step of the Leloir pathway. GALM enzyme activities were undetectable in lymphoblastoid cell lines established from two patients. Immunoblot analysis showed the absence of the GALM protein in the patients’ peripheral blood mononuclear cells. In vitro GALM expression and protein stability assays revealed altered stabilities of the variant GALM proteins. Conclusion: Biallelic GALM pathogenic variants cause galactosemia, suggesting the existence of type IV galactosemia.",
author = "Yoichi Wada and Atsuo Kikuchi and Natsuko Arai-Ichinoi and Osamu Sakamoto and Yusuke Takezawa and Shinya Iwasawa and Tetsuya Niihori and Hiromi Nyuzuki and Yoko Nakajima and Erika Ogawa and Mika Ishige and Hiroki Hirai and Hideo Sasai and Ryoji Fujiki and Matsuyuki Shirota and Ryo Funayama and Masayuki Yamamoto and Tetsuya Ito and Osamu Ohara and Keiko Nakayama and Yoko Aoki and Seizo Koshiba and Toshiyuki Fukao and Shigeo Kure",
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Wada, Y, Kikuchi, A, Arai-Ichinoi, N, Sakamoto, O, Takezawa, Y, Iwasawa, S, Niihori, T, Nyuzuki, H, Nakajima, Y, Ogawa, E, Ishige, M, Hirai, H, Sasai, H, Fujiki, R, Shirota, M, Funayama, R, Yamamoto, M, Ito, T, Ohara, O, Nakayama, K, Aoki, Y, Koshiba, S, Fukao, T & Kure, S 2019, 'Biallelic GALM pathogenic variants cause a novel type of galactosemia', Genetics in Medicine, vol. 21, no. 6, pp. 1286-1294. https://doi.org/10.1038/s41436-018-0340-x

Biallelic GALM pathogenic variants cause a novel type of galactosemia. / Wada, Yoichi; Kikuchi, Atsuo; Arai-Ichinoi, Natsuko; Sakamoto, Osamu; Takezawa, Yusuke; Iwasawa, Shinya; Niihori, Tetsuya; Nyuzuki, Hiromi; Nakajima, Yoko; Ogawa, Erika; Ishige, Mika; Hirai, Hiroki; Sasai, Hideo; Fujiki, Ryoji; Shirota, Matsuyuki; Funayama, Ryo; Yamamoto, Masayuki; Ito, Tetsuya; Ohara, Osamu; Nakayama, Keiko; Aoki, Yoko; Koshiba, Seizo; Fukao, Toshiyuki; Kure, Shigeo.

In: Genetics in Medicine, Vol. 21, No. 6, 01.06.2019, p. 1286-1294.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Biallelic GALM pathogenic variants cause a novel type of galactosemia

AU - Wada, Yoichi

AU - Kikuchi, Atsuo

AU - Arai-Ichinoi, Natsuko

AU - Sakamoto, Osamu

AU - Takezawa, Yusuke

AU - Iwasawa, Shinya

AU - Niihori, Tetsuya

AU - Nyuzuki, Hiromi

AU - Nakajima, Yoko

AU - Ogawa, Erika

AU - Ishige, Mika

AU - Hirai, Hiroki

AU - Sasai, Hideo

AU - Fujiki, Ryoji

AU - Shirota, Matsuyuki

AU - Funayama, Ryo

AU - Yamamoto, Masayuki

AU - Ito, Tetsuya

AU - Ohara, Osamu

AU - Nakayama, Keiko

AU - Aoki, Yoko

AU - Koshiba, Seizo

AU - Fukao, Toshiyuki

AU - Kure, Shigeo

PY - 2019/6/1

Y1 - 2019/6/1

N2 - Purpose: Galactosemia is caused by metabolic disturbances at various stages of galactose metabolism, including deficiencies in enzymes involved in the Leloir pathway (GALT, GALK1, and GALE). Nevertheless, the etiology of galactosemia has not been identified in a subset of patients. This study aimed to explore the causes of unexplained galactosemia. Methods: Trio-based exome sequencing and/or Sanger sequencing was performed in eight patients with unexplained congenital galactosemia. In vitro enzymatic assays and immunoblot assays were performed to confirm the pathogenicity of the variants. Results: The highest blood galactose levels observed in each patient were 17.3–41.9 mg/dl. Bilateral cataracts were observed in two patients. In all eight patients, we identified biallelic variants (p.Arg82*, p.Ile99Leufs*46, p.Gly142Arg, p.Arg267Gly, and p.Trp311*) in the GALM encoding galactose mutarotase, which catalyzes epimerization between β- and α-D-galactose in the first step of the Leloir pathway. GALM enzyme activities were undetectable in lymphoblastoid cell lines established from two patients. Immunoblot analysis showed the absence of the GALM protein in the patients’ peripheral blood mononuclear cells. In vitro GALM expression and protein stability assays revealed altered stabilities of the variant GALM proteins. Conclusion: Biallelic GALM pathogenic variants cause galactosemia, suggesting the existence of type IV galactosemia.

AB - Purpose: Galactosemia is caused by metabolic disturbances at various stages of galactose metabolism, including deficiencies in enzymes involved in the Leloir pathway (GALT, GALK1, and GALE). Nevertheless, the etiology of galactosemia has not been identified in a subset of patients. This study aimed to explore the causes of unexplained galactosemia. Methods: Trio-based exome sequencing and/or Sanger sequencing was performed in eight patients with unexplained congenital galactosemia. In vitro enzymatic assays and immunoblot assays were performed to confirm the pathogenicity of the variants. Results: The highest blood galactose levels observed in each patient were 17.3–41.9 mg/dl. Bilateral cataracts were observed in two patients. In all eight patients, we identified biallelic variants (p.Arg82*, p.Ile99Leufs*46, p.Gly142Arg, p.Arg267Gly, and p.Trp311*) in the GALM encoding galactose mutarotase, which catalyzes epimerization between β- and α-D-galactose in the first step of the Leloir pathway. GALM enzyme activities were undetectable in lymphoblastoid cell lines established from two patients. Immunoblot analysis showed the absence of the GALM protein in the patients’ peripheral blood mononuclear cells. In vitro GALM expression and protein stability assays revealed altered stabilities of the variant GALM proteins. Conclusion: Biallelic GALM pathogenic variants cause galactosemia, suggesting the existence of type IV galactosemia.

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Wada Y, Kikuchi A, Arai-Ichinoi N, Sakamoto O, Takezawa Y, Iwasawa S et al. Biallelic GALM pathogenic variants cause a novel type of galactosemia. Genetics in Medicine. 2019 Jun 1;21(6):1286-1294. https://doi.org/10.1038/s41436-018-0340-x