Diagnostic serum glycosylation profile in patients with intellectual disability as a result of MAN1B1 deficiency

Monique Van Scherpenzeel, Sharita Timal, Daisy Rymen, Alexander Hoischen, Manfred Wuhrer, Agnes Hipgrave-Ederveen, Stephanie Grunewald, Romain Peanne, Ann Saada, Shimon Edvardson, Sabine Grønborg, George Ruijter, Anna Kattentidt-Mouravieva, Jaime Moritz Brum, Mary Louise Freckmann, Susan Tomkins, Anil Jalan, Dagmar Prochazkova, Nina Ondruskova, Hana HansikovaMichel A. Willemsen, Paul J. Hensbergen, Gert Matthijs, Ron A. Wevers, Joris A. Veltman, Eva Morava-Kozicz, Dirk J. Lefeber

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Congenital disorders of glycosylation comprise a group of genetic defects with a high frequency of intellectual disability, caused by deficient glycosylation of proteins and lipids. The molecular basis of the majority of the congenital disorders of glycosylation type I subtypes, localized in the cytosol and endoplasmic reticulum, has been solved. However, elucidation of causative genes for defective Golgi glycosylation (congenital disorders of glycosylation type II) remains challenging because of a lack of sufficiently specific diagnostic serum methods. In a single patient with intellectual disability, whole-exome sequencing revealed MAN1B1 as congenital disorder of glycosylation type II candidate gene. A novel mass spectrometry method was applied for high-resolution glycoprofiling of intact plasma transferrin. A highly characteristic glycosylation signature was observed with hybrid type N-glycans, in agreement with deficient mannosidase activity. The speed and robustness of the method allowed subsequent screening in a cohort of 100 patients with congenital disorder of glycosylation type II, which revealed the characteristic glycosylation profile of MAN1B1-congenital disorder of glycosylation in 11 additional patients. Abnormal hybrid type N-glycans were also observed in the glycoprofiles of total serum proteins, of enriched immunoglobulins and of alpha1-antitrypsin in variable amounts. Sanger sequencing revealed MAN1B1 mutations in all patients, including severe truncating mutations and amino acid substitutions in the alpha-mannosidase catalytic site. Clinically, this group of patients was characterized by intellectual disability and delayed motor and speech development. In addition, variable dysmorphic features were noted, with truncal obesity and macrocephaly in ∼65% of patients. In summary, MAN1B1 deficiency appeared to be a frequent cause in our cohort of patients with unsolved congenital disorder of glycosylation type II. Our method for analysis of intact transferrin provides a rapid test to detect MAN1B1-deficient patients within congenital disorder of glycosylation type II cohorts and can be used as efficient diagnostic method to identify MAN1B1-deficient patients in intellectual disability cohorts. In addition, it provides a functional confirmation of MAN1B1 mutations as identified by next-generation sequencing in individuals with intellectual disability.

Original languageEnglish (US)
Pages (from-to)1030-1038
Number of pages9
JournalBrain
Volume137
Issue number4
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Fingerprint

Glycosylation
Intellectual Disability
Congenital Disorders of Glycosylation
Serum
Transferrin
Mutation
Polysaccharides
Mannosidases
Megalencephaly
alpha-Mannosidase
Exome
Amino Acid Substitution
Endoplasmic Reticulum
Cytosol
Genes
Immunoglobulins
Blood Proteins
Mass Spectrometry
Catalytic Domain
Obesity

Keywords

  • biomarker
  • congenital disorders of glycosylation
  • glycomics
  • intellectual disability
  • MAN1B1 (EC 3.2.1.113)

ASJC Scopus subject areas

  • Clinical Neurology
  • Medicine(all)

Cite this

Van Scherpenzeel, M., Timal, S., Rymen, D., Hoischen, A., Wuhrer, M., Hipgrave-Ederveen, A., ... Lefeber, D. J. (2014). Diagnostic serum glycosylation profile in patients with intellectual disability as a result of MAN1B1 deficiency. Brain, 137(4), 1030-1038. https://doi.org/10.1093/brain/awu019

Diagnostic serum glycosylation profile in patients with intellectual disability as a result of MAN1B1 deficiency. / Van Scherpenzeel, Monique; Timal, Sharita; Rymen, Daisy; Hoischen, Alexander; Wuhrer, Manfred; Hipgrave-Ederveen, Agnes; Grunewald, Stephanie; Peanne, Romain; Saada, Ann; Edvardson, Shimon; Grønborg, Sabine; Ruijter, George; Kattentidt-Mouravieva, Anna; Brum, Jaime Moritz; Freckmann, Mary Louise; Tomkins, Susan; Jalan, Anil; Prochazkova, Dagmar; Ondruskova, Nina; Hansikova, Hana; Willemsen, Michel A.; Hensbergen, Paul J.; Matthijs, Gert; Wevers, Ron A.; Veltman, Joris A.; Morava-Kozicz, Eva; Lefeber, Dirk J.

In: Brain, Vol. 137, No. 4, 01.01.2014, p. 1030-1038.

Research output: Contribution to journalArticle

Van Scherpenzeel, M, Timal, S, Rymen, D, Hoischen, A, Wuhrer, M, Hipgrave-Ederveen, A, Grunewald, S, Peanne, R, Saada, A, Edvardson, S, Grønborg, S, Ruijter, G, Kattentidt-Mouravieva, A, Brum, JM, Freckmann, ML, Tomkins, S, Jalan, A, Prochazkova, D, Ondruskova, N, Hansikova, H, Willemsen, MA, Hensbergen, PJ, Matthijs, G, Wevers, RA, Veltman, JA, Morava-Kozicz, E & Lefeber, DJ 2014, 'Diagnostic serum glycosylation profile in patients with intellectual disability as a result of MAN1B1 deficiency', Brain, vol. 137, no. 4, pp. 1030-1038. https://doi.org/10.1093/brain/awu019
Van Scherpenzeel M, Timal S, Rymen D, Hoischen A, Wuhrer M, Hipgrave-Ederveen A et al. Diagnostic serum glycosylation profile in patients with intellectual disability as a result of MAN1B1 deficiency. Brain. 2014 Jan 1;137(4):1030-1038. https://doi.org/10.1093/brain/awu019
Van Scherpenzeel, Monique ; Timal, Sharita ; Rymen, Daisy ; Hoischen, Alexander ; Wuhrer, Manfred ; Hipgrave-Ederveen, Agnes ; Grunewald, Stephanie ; Peanne, Romain ; Saada, Ann ; Edvardson, Shimon ; Grønborg, Sabine ; Ruijter, George ; Kattentidt-Mouravieva, Anna ; Brum, Jaime Moritz ; Freckmann, Mary Louise ; Tomkins, Susan ; Jalan, Anil ; Prochazkova, Dagmar ; Ondruskova, Nina ; Hansikova, Hana ; Willemsen, Michel A. ; Hensbergen, Paul J. ; Matthijs, Gert ; Wevers, Ron A. ; Veltman, Joris A. ; Morava-Kozicz, Eva ; Lefeber, Dirk J. / Diagnostic serum glycosylation profile in patients with intellectual disability as a result of MAN1B1 deficiency. In: Brain. 2014 ; Vol. 137, No. 4. pp. 1030-1038.
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abstract = "Congenital disorders of glycosylation comprise a group of genetic defects with a high frequency of intellectual disability, caused by deficient glycosylation of proteins and lipids. The molecular basis of the majority of the congenital disorders of glycosylation type I subtypes, localized in the cytosol and endoplasmic reticulum, has been solved. However, elucidation of causative genes for defective Golgi glycosylation (congenital disorders of glycosylation type II) remains challenging because of a lack of sufficiently specific diagnostic serum methods. In a single patient with intellectual disability, whole-exome sequencing revealed MAN1B1 as congenital disorder of glycosylation type II candidate gene. A novel mass spectrometry method was applied for high-resolution glycoprofiling of intact plasma transferrin. A highly characteristic glycosylation signature was observed with hybrid type N-glycans, in agreement with deficient mannosidase activity. The speed and robustness of the method allowed subsequent screening in a cohort of 100 patients with congenital disorder of glycosylation type II, which revealed the characteristic glycosylation profile of MAN1B1-congenital disorder of glycosylation in 11 additional patients. Abnormal hybrid type N-glycans were also observed in the glycoprofiles of total serum proteins, of enriched immunoglobulins and of alpha1-antitrypsin in variable amounts. Sanger sequencing revealed MAN1B1 mutations in all patients, including severe truncating mutations and amino acid substitutions in the alpha-mannosidase catalytic site. Clinically, this group of patients was characterized by intellectual disability and delayed motor and speech development. In addition, variable dysmorphic features were noted, with truncal obesity and macrocephaly in ∼65{\%} of patients. In summary, MAN1B1 deficiency appeared to be a frequent cause in our cohort of patients with unsolved congenital disorder of glycosylation type II. Our method for analysis of intact transferrin provides a rapid test to detect MAN1B1-deficient patients within congenital disorder of glycosylation type II cohorts and can be used as efficient diagnostic method to identify MAN1B1-deficient patients in intellectual disability cohorts. In addition, it provides a functional confirmation of MAN1B1 mutations as identified by next-generation sequencing in individuals with intellectual disability.",
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AU - Van Scherpenzeel, Monique

AU - Timal, Sharita

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AU - Hoischen, Alexander

AU - Wuhrer, Manfred

AU - Hipgrave-Ederveen, Agnes

AU - Grunewald, Stephanie

AU - Peanne, Romain

AU - Saada, Ann

AU - Edvardson, Shimon

AU - Grønborg, Sabine

AU - Ruijter, George

AU - Kattentidt-Mouravieva, Anna

AU - Brum, Jaime Moritz

AU - Freckmann, Mary Louise

AU - Tomkins, Susan

AU - Jalan, Anil

AU - Prochazkova, Dagmar

AU - Ondruskova, Nina

AU - Hansikova, Hana

AU - Willemsen, Michel A.

AU - Hensbergen, Paul J.

AU - Matthijs, Gert

AU - Wevers, Ron A.

AU - Veltman, Joris A.

AU - Morava-Kozicz, Eva

AU - Lefeber, Dirk J.

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N2 - Congenital disorders of glycosylation comprise a group of genetic defects with a high frequency of intellectual disability, caused by deficient glycosylation of proteins and lipids. The molecular basis of the majority of the congenital disorders of glycosylation type I subtypes, localized in the cytosol and endoplasmic reticulum, has been solved. However, elucidation of causative genes for defective Golgi glycosylation (congenital disorders of glycosylation type II) remains challenging because of a lack of sufficiently specific diagnostic serum methods. In a single patient with intellectual disability, whole-exome sequencing revealed MAN1B1 as congenital disorder of glycosylation type II candidate gene. A novel mass spectrometry method was applied for high-resolution glycoprofiling of intact plasma transferrin. A highly characteristic glycosylation signature was observed with hybrid type N-glycans, in agreement with deficient mannosidase activity. The speed and robustness of the method allowed subsequent screening in a cohort of 100 patients with congenital disorder of glycosylation type II, which revealed the characteristic glycosylation profile of MAN1B1-congenital disorder of glycosylation in 11 additional patients. Abnormal hybrid type N-glycans were also observed in the glycoprofiles of total serum proteins, of enriched immunoglobulins and of alpha1-antitrypsin in variable amounts. Sanger sequencing revealed MAN1B1 mutations in all patients, including severe truncating mutations and amino acid substitutions in the alpha-mannosidase catalytic site. Clinically, this group of patients was characterized by intellectual disability and delayed motor and speech development. In addition, variable dysmorphic features were noted, with truncal obesity and macrocephaly in ∼65% of patients. In summary, MAN1B1 deficiency appeared to be a frequent cause in our cohort of patients with unsolved congenital disorder of glycosylation type II. Our method for analysis of intact transferrin provides a rapid test to detect MAN1B1-deficient patients within congenital disorder of glycosylation type II cohorts and can be used as efficient diagnostic method to identify MAN1B1-deficient patients in intellectual disability cohorts. In addition, it provides a functional confirmation of MAN1B1 mutations as identified by next-generation sequencing in individuals with intellectual disability.

AB - Congenital disorders of glycosylation comprise a group of genetic defects with a high frequency of intellectual disability, caused by deficient glycosylation of proteins and lipids. The molecular basis of the majority of the congenital disorders of glycosylation type I subtypes, localized in the cytosol and endoplasmic reticulum, has been solved. However, elucidation of causative genes for defective Golgi glycosylation (congenital disorders of glycosylation type II) remains challenging because of a lack of sufficiently specific diagnostic serum methods. In a single patient with intellectual disability, whole-exome sequencing revealed MAN1B1 as congenital disorder of glycosylation type II candidate gene. A novel mass spectrometry method was applied for high-resolution glycoprofiling of intact plasma transferrin. A highly characteristic glycosylation signature was observed with hybrid type N-glycans, in agreement with deficient mannosidase activity. The speed and robustness of the method allowed subsequent screening in a cohort of 100 patients with congenital disorder of glycosylation type II, which revealed the characteristic glycosylation profile of MAN1B1-congenital disorder of glycosylation in 11 additional patients. Abnormal hybrid type N-glycans were also observed in the glycoprofiles of total serum proteins, of enriched immunoglobulins and of alpha1-antitrypsin in variable amounts. Sanger sequencing revealed MAN1B1 mutations in all patients, including severe truncating mutations and amino acid substitutions in the alpha-mannosidase catalytic site. Clinically, this group of patients was characterized by intellectual disability and delayed motor and speech development. In addition, variable dysmorphic features were noted, with truncal obesity and macrocephaly in ∼65% of patients. In summary, MAN1B1 deficiency appeared to be a frequent cause in our cohort of patients with unsolved congenital disorder of glycosylation type II. Our method for analysis of intact transferrin provides a rapid test to detect MAN1B1-deficient patients within congenital disorder of glycosylation type II cohorts and can be used as efficient diagnostic method to identify MAN1B1-deficient patients in intellectual disability cohorts. In addition, it provides a functional confirmation of MAN1B1 mutations as identified by next-generation sequencing in individuals with intellectual disability.

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