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CRYAB gene

Overview

Gene (OMIM No.)
Function of gene/protein
  • Protein: crystallin alpha B
  • Lens protein with structural and functional components
  • Highly organized, compact structures that contribute to the refractive index of the lens
  • Interacts with other crystallins help to maintain lens transparency
  • Also highly expressed in cardiac and skeletal muscles
  • Functions as a molecular chaperone for desmin and actin
Clinical phenotype
(OMIM phenotype no.)
  • Cataract 16, multiple types (#613763)
  • Syndromic cataract: myopathy, myofibrillar 2 (#608810)
  • Cardiomyopathy, dilated, 1II (#615184)
  • Myopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin related (#613869)
Inheritance
  • Autosomal recessive
  • Autosomal dominant (most common)
Ocular features
  • Isolated congenital cataracts (nuclear, posterior polar or lamellar)
  • Adult-onset cataracts in the myopathy, myofibrillar 2 phenotype
Systemic featuresMyopathy, myofibrillar, 2:
  • Patients usually present in middle age with neurological symptoms
  • Progressive muscular weakness (proximal and distal muscles in lower and upper limbs)
  • Respiratory insufficiency
  • Cardiomyopathy
  • Dysphagia
  • Dysphonia
Key investigations
  • B-scan USS to measure axial length to document microphthalmia and detect any posterior segment abnormalities
  • Electrophysiology
  • TORCH screen
  • MRI brain and orbit
  • Systemic assessment by relevant specialists if extraocular features are present
  • Electrocardiogram and echocardiogram
  • Muscle biopsies
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (cataract)
  • Whole exome sequencing
  • Whole genome sequencing
ManagementOcularSystemic
  • Multidisciplinary approach
Therapies under research
  • None at present
Further information

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Additional information

The phenotypes associated with CYRAB mutations are clinically heterogenous. A partial genotype-phenotype relationship can be observed.

Heterozygous (autosomal dominant) variants in different locations of the CRYAB gene can result in different phenotypes. Mutations in exon 1 (a 1-base pair deletion 450delA and p.Pro20Ser) are associated with an isolated cataract phenotype[1,2], while mutations in exon 3 can cause isolated cataract (p.Asp140Asn)[3], isolated late-onset mild dilated cardiomyopathy (p.Arg157His and p.Gly154Ser)[4,5]or a multisystemic muscular dystrophy with adult-onset lens opacities (p.Asp109His, p.Arg120Gly and p.Gly151Ter).[6-8]

Autosomal recessive missense mutation (p.Arg56Trp) of CRYAB causes isolated cataract[9] while the truncating mutation p.Ser21Ala, a founder mutation reported in Canadian aboriginals of Cree descent, is associated with a severe phenotype called fatal hypertonic infantile muscular dystrophy (OMIM #613869).[10] This condition is characterised by early (first few weeks of life) and rapidly progressive limb and axial muscle stiffness, with increasing severe respiratory difficulty resulting in death before 3 years of age.

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References

  1.  Berry V, Francis P, Reddy MA, et al. Alpha-B crystallin gene (CRYAB) mutation causes dominant congenital posterior polar cataract in humans. Am J Hum Genet. 2001;69(5):1141‐1145
  2.  Liu M, Ke T, Wang Z, et al. Identification of a CRYAB mutation associated with autosomal dominant posterior polar cataract in a Chinese family. Invest Ophthalmol Vis Sci. 2006;47(8):3461‐3466
  3.  Liu Y, Zhang X, Luo L, et al. A novel alphaB-crystallin mutation associated with autosomal dominant congenital lamellar cataract. Invest Ophthalmol Vis Sci. 2006;47(3):1069‐1075
  4.  Inagaki N, Hayashi T, Arimura T, et al. Alpha B-crystallin mutation in dilated cardiomyopathy. Biochem Biophys Res Commun. 2006;342(2):379-386
  5.  Pilotto A, Marziliano N, Pasotti M, Grasso M, Costante AM, Arbustini E. alphaB-crystallin mutation in dilated cardiomyopathies: low prevalence in a consecutive series of 200 unrelated probands. Biochem Biophys Res Commun. 2006;346(4):1115-1117
  6.  Vicart P, Caron A, Guicheney P, et al. A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy. Nat Genet. 1998;20(1):92-95
  7.  Selcen D, Engel AG. Myofibrillar myopathy caused by novel dominant negative alpha B-crystallin mutations. Ann Neurol. 2003;54(6):804-810
  8.  Sacconi S, Féasson L, Antoine JC, et al. A novel CRYAB mutation resulting in multisystemic disease. Neuromuscul Disord. 2012;22(1):66‐72
  9.  Safieh LA, Khan AO, Alkuraya FS. Identification of a novel CRYAB mutation associated with autosomal recessive juvenile cataract in a Saudi family. Mol Vis. 2009;15:980‐984
  10.  Del Bigio MR, Chudley AE, Sarnat HB, et al. Infantile muscular dystrophy in Canadian aboriginals is an αB-crystallinopathy. Ann Neurol. 2011;69(5):866-871
  11.  Chávez Zobel AT, Loranger A, Marceau N, Thériault JR, Lambert H, Landry J. Distinct chaperone mechanisms can delay the formation of aggresomes by the myopathy-causing R120G alphaB-crystallin mutant. Hum Mol Genet. 2003;12(13):1609‐1620
  12.  Wang X, Osinska H, Klevitsky R, et al. Expression of R120G-alphaB-crystallin causes aberrant desmin and alphaB-crystallin aggregation and cardiomyopathy in mice. Circ Res. 2001;89(1):84-91

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Updated on November 30, 2020
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