NHGRI logo
Staff Scientist

Medical Genetics Branch


B.Sc. Wageningen University, Netherlands, 1990

M.Sc. Wageningen University, Netherlands, 1992

Ph.D. Nijmegen University, Netherlands, 1998


Dr. Huizing investigates rare human genetic disorders and associated intracellular processes in order to gain insight into the changes in molecular function that underlie various genetic metabolic disorders, with the hope of developing treatments for these illnesses. Her research focuses on disorders of sialic acid metabolism and of lysosome-related organelles.

Sialic acid is a negatively charged sugar localized at the end of glycoconjugate chains on glycoproteins and glycolipids. These chains are present on the cell surface and are crucial for many biological processes, including cell adhesion and signal transduction. Sialic acid synthesis is tightly regulated; defects in this pathway cause a variety of disorders, including hereditary inclusion body myopathy (HIBM), sialuria, infantile sialic acid storage disease (ISSD), and Salla disease.

HIBM is caused by mutations in the gene encoding the key enzyme in sialic acid synthesis, UDP-GlcNAc 2-epimerase/ManNAc kinase, which in turn leads to sialic acid deficiency. Without adequate supplies of sialic acid, progressive muscle degeneration (or myopathy) sets in. Dr. Huizing has demonstrated that muscle ?-dystroglycan, an integral component of the muscle transmembrane dystrophin-glycoprotein complex, is low in sialic acid in HIBM patients. Based on this observation, they developed a mouse model mimicking HIBM. These mice die of unexpected glomerular disease due to hyposialylation of kidney glycoproteins, leading to severe proteinuria and hematuria. Oral administration of the sialic acid precursor N-acetyl-mannosamine (ManNAc) partially rescues the kidney defect, allowing the mutant mice to survive. Dr. Huizing is currently evaluating the use of ManNAc not only as a treatment for HIBM, but also for renal disorders involving glomerular disease-associated proteinuria and hematuria.

Dr. Huizing also studies other sialic acid-related diseases, including sialuria, a progressive disease in which patients produce excess sialic acid. Symptoms can include developmental delay, coarse features, and liver enlargement. Sialuria appears to be due to a single mutation that causes a change in the three-dimensional structure of the active site of the UDP-GlcNAc 2-epimerase/ManNAc kinase enzyme. Dr. Huizing demonstrated that elimination of the single mutant allele using a synthetic small interfering RNA (siRNA) rescued the abnormal phenotype in cultured cells from sialuria patients. In ISSD and Salla disease, other sialic acid-related conditions, a transport malfunction causes sialic acid to accumulate in lysosomes. Dr. Huizing is evaluating possible steps to alleviate this sialic acid accumulation in cultured cells from ISSD and Salla patients.

Dr. Huizing is also investigating the causes of and potential treatments for disorders of lysosome-related organelles (LROs), including Hermansky-Pudlak syndrome (HPS), Chediak-Higashi syndrome, and Griscelli syndrome. A rare inherited disorder that has been identified in about 400 people worldwide, HPS is mainly characterized by decreased pigmentation (ocular or cutaneous albinism) and a lack of platelet dense bodies that causes bleeding problems. The disease can lead to prolonged bleeding and poor function of the lungs and intestine; fatal pulmonary fibrosis is a possible complication. An ongoing clinical trial at NHGRI is testing the drug pirfenidone as a potential HPS treatment for symptoms associated with pulmonary fibrosis.

Dr. Huizing continues to search for novel genes causing LRO disorders, with the hope of better understanding the biological causes of these conditions. She played a major role in identifying six distinct genetic subgroups of HPS patients by cataloging relevant clinical and genetic characteristics. To study the effects of LRO-related gene mutations, Dr. Huizing is performing fluorescent protein expression studies using patients' cells in order to examine defective intracellular trafficking. These results will be instructive for elucidating the complex vesicular transport processes that are involved in the biogenesis of LROs.


Huizing M., Anikster Y., Fitzpatrick D.L., Jeong A.B., D'Souza M., Rausche M., Toro J.R., Kaiser-Kupfer M.I., White J.G., Gahl W.A. Hermansky-Pudlak syndrome type 3 in Ashkenazi Jews and other non-Puerto Rican patients with hypopigmentation and platelet storage-pool deficiency. Am J Hum Genet, 69:1022-1032. 2001. [PubMed]

Huizing M., Gahl W.A. Disorders of vesicles of lysosomal lineage: the Hermansky-Pudlak syndromes. Curr Mol Med, 2:451-467. 2002. [PubMed]

Huizing M., Scher C.D., Strovel E., Fitzpatrick D.L., Hartnell L.M., Anikster Y., Gahl W.A. Nonsense mutations in ADTB3A cause complete deficiency of the beta3A subunit of adaptor complex-3 and severe Hermansky-Pudlak syndrome type 2. Pediatr Res, 51:150-158. 2002. [PubMed]

Huizing M., Hess R., Dorward H., Claassen D.A., Helip-Wooley A., Kleta R., Kaiser-Kupfer M.I., White J.G., Gahl W.A. Cellular, molecular and clinical characterization of patients with Hermansky-Pudlak syndrome type 5. Traffic, 5:711-22. 2004. [PubMed]

Huizing M., Rakocevic G., Sparks S.E., Mamali I., Shatunov A., Goldfarb L., Krasnewich D., Gahl W.A., Dalakas M.C. Hypoglycosylation of alpha-dystroglycan in patients with hereditary IBM due to GNE mutations. Mol Genet Metab, 81:196-202. 2004. [PubMed]

Helip-Wooley A, Westbroek W, Dorward H, Mommaas M, Boissy RE, Gahl WA, Huizing M. Association of the Hermansky-Pudlak syndrome type-3 protein with clathrin. BMC Cell Biol, 6:33. 2005. [PubMed]

Sparks SE, Ciccone C, Lalor M, Orvisky E, Klootwijk R, Savelkoul PJ, Dalakas MC, Krasnewich DM, Gahl WA, Huizing M. Use of a cell-free system to determine UDP-N-acetylglucosamine 2-epimerase and N-acetylmannosamine kinase activities in human Hereditary Inclusion Body Myopathy. Glycobiology, 15:1102-1110. 2005. [PubMed]

Galeano B, Klootwijk R, Manoli I, Sun MS, Ciccone C, Darvish D, Starost MF, Zerfas PM, Hoffmann VJ, Hoogstraten-Miller S, Krasnewich DM, Gahl WA, Huizing M. Mutation in the key enzyme of sialic acid biosynthesis causes severe glomerular proteinuria and is rescued by N-acetylmannosamine. Journal of Clinical Investigation, 17:1585-1594. 2007. [PubMed]

Huizing M, Helip-Wooley A, Westbroek W, Gunay-Aygun M, Gahl WA. Disorders of Lysosome-related Organelle Biogenesis: Clinical and Molecular Genetics. Annual Reviews of Genomics and Human Genetics, 9:359-86. 2008. [PubMed]

Klootwijk R.D., Savelkoul P.J.M., Ciccone C., Manoli I., Caplen N.J., Krasnewich D.M., Gahl W.A., Huizing M. Allele-specific silencing of the dominant disease allele in sialuria by RNA interference. FASEB J, 22:3846-3852. 2008. [PubMed]

Huizing M., Krasnewich D.M. Hereditary Inclusion Body myopathy: A decade of progress. Biochim Biophys Acta, 1792: 881-887. 2009. [PubMed]

Huizing M., Dorward H., Ly L., Klootwijk R., Kleta R., Skovby F., Pei W., Feldman B., Gahl W.A., Anikster Y. OPA3, mutated in 3-methylglutaconic aciduria type III, encodes two transcripts targeted primarily to mitochondria. Molecular Genetics and Metabolism, 100: 149-154. 2010. [PubMed]

Kurochkina N, Yardeni T, Huizing M. Molecular modeling of the bifunctional enzyme uridine diphosphate-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase and predictions of structural effects of mutations associated with HIBM and sialuria. Gycobiology, 20:322-337. 2010. [PubMed]

Cullinane AR, Curry JA, Carmona-Rivera C, Summers CG, Ciccone C, Cardillo ND, Dorward H, Hess RA, White JG, Adams D, Huizing M, Gahl WA. A BLOC-1 Mutation Screen Reveals that PLDN is Mutated in Hermanksy-Pudlak Syndrome Type 9. Am J Hum Genet, 88:778-787. 2011. [PubMed]

Vilboux T, Ciccone C, Blancato JK, Cox GF, Deshpande C, Introne WJ, Gahl WA, Smith ACM, Huizing M. Molecular Analysis of the Retinoic Acid Induced 1 Gene (RAI1) in Patients with Suspected Smith-Magenis Syndrome without the 17p11.2 Deletion. PLoS ONE, 6:e22861. 2011. [PubMed Central]

Yardeni T, Choekyi T, Jacobs K, Ciccone C, Patzel K, Anikster Y, Gahl WA, Kurochkina N, Huizing M. Identification, Tissue Distribution and Molecular Modeling of Novel Human Isoforms of the Key Enzyme in Sialic Acid Synthesis, UDP-GlcNAc 2-epimerase/ManNAc Kinase. Biochemistry, 50:8914-8925. 2011. [PubMed]

Kakani S, Yardeni T, Poling J, Ciccone C, Niethamer T, Klootwijk RD, Manoli I, Darvish D, Hoogstraten-Miller S, Zerfas P, Tian E, Ten Hagen KG, Kopp JB, Gahl WA, Huizing M. The Gne M712T mouse as a model for human glomerulopathy. Am J Pathol, 2012. [In Press]

Book Chapters:

Boissy RE, Huizing M, Gahl WA. Biogenesis of Melanosomes, Section 2 (7). In: The Pigmentary System: Physiology and Pathophysiology (JJ. Nordlund, RE Boissy, VJ Hearing, RA King, WS Oetting, J-P Ortonne, eds) Oxford: Blackwell Publishing, May 2006. ISBN: 1405120347. pp. 155-170.

Last updated: October 16, 2015