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 language | English |
|---|---|
| Pages (from-to) | 1286-1294 |
| Number of pages | 9 |
| Journal | Genetics in Medicine |
| Volume | 21 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 01-06-2019 |
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All Science Journal Classification (ASJC) codes
- Genetics(clinical)
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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 journal › Article
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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U2 - 10.1038/s41436-018-0340-x
DO - 10.1038/s41436-018-0340-x
M3 - Article
C2 - 30451973
AN - SCOPUS:85055249201
VL - 21
SP - 1286
EP - 1294
JO - Genetics in Medicine
JF - Genetics in Medicine
SN - 1098-3600
IS - 6
ER -