Question 1

What are some gene mutations that cause non-HFE forms of hereditary hemochromatosis (HH)?

William Aird · Accepted Answer

Mutations in:

Hepcidin
Hemojuvelin
Transferrin receptor 2
Ferroportin

Classification of hereditary hemochromatosis:

Classification	Genes involved	Inheritance	Protein function	Clinical manifestations
Type 1A HH (homozygote)	Mutations in HFE: C282Y	AR	Involved in hepcidin synthesis via BMP6, interaction with TFR1.	Arthropathy, skin pigmentation, liver damage, diabetes mellitus, endocrine dysfunction, cardiomyopathy, hypogonadism.
Type 1B HH (compound heterozygote)	Mutations in HFE: C282Y H63D	AR	Involved in hepcidin synthesis via BMP6, interaction with TFR1.	Arthropathy, skin pigmentation, liver damage, diabetes mellitus, endocrine dysfunction, cardiomyopathy, hypogonadism.
Type 1C HH	Mutations in HFE: S65C	AR		Possible elevations in serum iron/ ferritin, no evidence of tissue iron deposition.
Type 2A juvenile HH	HJV (hemojuvelin)	AR	Involved in hepcidin synthesis, BMP co-receptor.	Earlier onset, ,30 years old, hypogonadism and cardiomyopathy are prevalent.
Type 2B juvenile HH	HAMP (hepcidin)	AR	Downregulation of iron efflux from erythrocytes.	Earlier onset, ,30 years old, hypogonadism and cardiomyopathy are prevalent.
Type 3 HH	TFR2 (transferrin receptor 2)	AR	Involved in hepcidin synthesis, interaction with transferrin.	Arthropathy, skin pigmentation, liver damage, diabetes mellitus, endocrine dysfunction, cardiomyopathy, hypogonadism.
Type 4A HH (FPN disease)	SLC40A1 (FPN)	AD	Duodenal iron export.	Iron deposition in the spleen is very common, lower tolerance to phlebotomies and may have anemia.
Type 4B HH (nonclassical FPN disease)	SLC40A1 (FPN)	AD	Resistance to hepcidin.	Fatigue, joint pain.

AD, automosomal dominant; AR, autosomal recessive; FPN, ferroportin; HAMP, hepatic antimicrobial protein; HH, hereditary hemochromatosis. From Am J Gastroenterol 2019;114:1202–1218.