Hereditary spherocytosis causes

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• Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:

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Overview

• HS is caused by a variety of mutations that cause defects in red blood cell (RBC) membrane proteins. HS usually is transmitted as an autosomal dominant trait, and the identification of the disorder in multiple generations of affected families is the rule.

Causes

• Hereditary spherocytosis is caused by a variety of genetic mutations.
• There are 05 genes associated with hereditary spherocytosis including, alpha spectrin (SPTA1), beta spectrin (SPTB), ankyrin (ANK1), band3 (SLC4A1) and protein 4.2 (EPB42).
• Mutations in one or more of hereditary spherocytosis related genes can cause membrane protein deficiency leading to hereditary spherocytosis.

Molecular and Genetic Characteristics of 5 Erythrocyte Membrane Protein Genes

Gene	Chromosome Location	Membrane Protein	Prevalent Mutations	Heredity	Associated Disease
ANK1	8p11.2	Ankyrin-1	frameshift, nonsense, splicing, novel mutations	autosomal dominant, autosomal recessive	hereditary spherocytosis
SLC4A1	17q21	Band3	missense,frameshift,polymorphism	autosomal dominant	hereditary spherocytosis,distal renal tubular acisosis
SPTA1	1q22-q23	alpha spectrin	SpaLEPRA allele, splicing, frameshift	autosomal recessive	hereditary spherocytosis, hereditary eliptocytosis, hereditary pyropoikilocytosis
SPTB	14q23-q24.1	beta spectrin	splicing, frameshift, nonsense, novel mutations	autosomal dominant	hereditary spherocytosis, hereditary eliptocytosis, hereditary pyropoikilocytosis
EBP42	15q15-q21	protein 4.2	missense, nonsense	autosomal recessive	hereditary spherocytosis

• HS is caused by a variety of mutations that lead to defects in red blood cell (RBC) membrane proteins. HS usually is transmitted as an autosomal dominant trait, and the identification of the disorder in multiple generations of affected families is the rule. Homozygosity for this dominantly transmitted HS gene has not been identified, which suggests that the homozygous state is incompatible with life.

• Twenty-five percent of all newly diagnosed patients do not demonstrate a dominant inheritance pattern. Parents of these patients do not have clinical or hematologic abnormalities. Some of these sporadic cases may result from new mutations.

• An autosomal recessive mode of inheritance also occurs, as indicated by descriptions of families in which apparently healthy parents have had more than one affected child. Recessive inheritance may account for 20-25% of all HS cases. It manifests only in individuals who are homozygous or compound heterozygous and often is associated with severe hemolytic anemia.