Ankyrin–1 mutations are a major cause of dominant and recessive hereditary spherocytosis View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

1996-06

AUTHORS

Stefan W. Eber, Jennifer M. Gonzalez, Marcia L. Lux, Alphonse L. Scarpa, William T. Tse, Marion Dornwell, Jutta Herbers, Wilfried Kugler, Refik Ozcan, Arnulf Pekrun, Patrick G. Gallagher, Werner Schroter, Bernard G. Forget, Samuel E. Lux

ABSTRACT

Hereditary spherocytosis (HS) is the most common inherited haemolytic anaemia in Northern Europeans. The primary molecular defects reside in the red blood cell (RBC) membrane, particularly in proteins that link the membrane skeleton to the overlying lipid bilayer and its integral membrane constituents1. Ankyrin-1 is the predominant linker molecule. It attaches spectrin, the major skeletal protein, to the cytoplasmic domain of band 3, the RBC anion exchanger. Two-thirds of patients with HS have combined spectrin and ankyrin-1 deficiency2,3; deficiency of band 3 occurs in about 15 to 20% (ref. 1). These data suggest that ankyrin-1 or band 3 defects may be common in HS. To test this we screened all 42 coding exons plus the 5′ untranslated/promoter region of ankyrin-1 and the 19 coding exons of band 3 in 46 HS families. Twelve ankyrin-1 mutations and five band 3 mutations were identified. Missense mutations and a mutation in the putative ankyrin-1 promoter were common in recessive HS. In contrast, ankyrin-1 and band 3 frameshift and nonsense null mutations prevailed in dominant HS. Increased accu-mulation of the normal protein product partially compensated for the ankyrin-1 or band 3 defects in some of these null mutations. Our findings indi-cate that ankyrin-1 mutations are a major cause of dominant and recessive HS (∼35 to 65%), that band 3 mutations are less common (∼15 to 25%), and that the severity of HS is modified by factors other than the primary gene defect. More... »

PAGES

214-218

Journal

TITLE

Nature Genetics

ISSUE

2

VOLUME

13

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/ng0696-214

DOI

http://dx.doi.org/10.1038/ng0696-214

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1034029330

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/8640229


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26 schema:description Hereditary spherocytosis (HS) is the most common inherited haemolytic anaemia in Northern Europeans. The primary molecular defects reside in the red blood cell (RBC) membrane, particularly in proteins that link the membrane skeleton to the overlying lipid bilayer and its integral membrane constituents1. Ankyrin-1 is the predominant linker molecule. It attaches spectrin, the major skeletal protein, to the cytoplasmic domain of band 3, the RBC anion exchanger. Two-thirds of patients with HS have combined spectrin and ankyrin-1 deficiency2,3; deficiency of band 3 occurs in about 15 to 20% (ref. 1). These data suggest that ankyrin-1 or band 3 defects may be common in HS. To test this we screened all 42 coding exons plus the 5′ untranslated/promoter region of ankyrin-1 and the 19 coding exons of band 3 in 46 HS families. Twelve ankyrin-1 mutations and five band 3 mutations were identified. Missense mutations and a mutation in the putative ankyrin-1 promoter were common in recessive HS. In contrast, ankyrin-1 and band 3 frameshift and nonsense null mutations prevailed in dominant HS. Increased accu-mulation of the normal protein product partially compensated for the ankyrin-1 or band 3 defects in some of these null mutations. Our findings indi-cate that ankyrin-1 mutations are a major cause of dominant and recessive HS (∼35 to 65%), that band 3 mutations are less common (∼15 to 25%), and that the severity of HS is modified by factors other than the primary gene defect.
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35 accu-mulation
36 anemia
37 anion exchanger
38 ankyrin 1
39 ankyrin-1 mutations
40 band 3
41 band 3 defects
42 band 3 mutations
43 bilayers
44 blood cell membranes
45 cause
46 cell membrane
47 contrast
48 cytoplasmic domain
49 data
50 defects
51 deficiency
52 domain
53 dominant hereditary spherocytosis
54 exchanger
55 exons
56 factors
57 family
58 findings
59 gene defects
60 haemolytic anaemia
61 hereditary spherocytosis
62 linker molecules
63 lipid bilayers
64 major cause
65 major skeletal protein
66 membrane
67 membrane skeleton
68 missense mutations
69 molecular defects
70 molecules
71 mutations
72 normal protein product
73 null mutation
74 patients
75 primary gene defect
76 primary molecular defect
77 products
78 promoter
79 promoter region
80 protein
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82 recessive hereditary spherocytosis
83 red blood cell membrane
84 region
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86 skeletal proteins
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