Original Investigation

Human Genetics

, Volume 128, Issue 4, pp 365-371

First online:

A homozygous mutation in LTBP2 causes isolated microspherophakia

  • Arun KumarAffiliated withDepartment of Molecular Reproduction, Development and Genetics, Indian Institute of Science Email author 
  • , Maheswara R. DuvvariAffiliated withDepartment of Molecular Reproduction, Development and Genetics, Indian Institute of Science
  • , Venkatesh C. PrabhakaranAffiliated withMinto Ophthalmic Hospital
  • , Jyoti S. ShettyAffiliated withBangalore West Lions Superspecialty Eye Hospital
  • , Gowri J. MurthyAffiliated withPrabha Eye Clinic
  • , Susan H. BlantonAffiliated withMiami Institute for Human Genomics, University of Miami Miller School of Medicine

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Microspherophakia is an autosomal-recessive congenital disorder characterized by small spherical lens. It may be isolated or occur as part of a hereditary systemic disorder, such as Marfan syndrome, autosomal dominant and recessive forms of Weill-Marchesani syndrome, autosomal dominant glaucoma–lens ectopia–microspherophakia–stiffness–shortness syndrome, autosomal dominant microspherophakia with hernia, and microspherophakia-metaphyseal dysplasia. The purpose of this study was to map and identify the gene for isolated microspherophakia in two consanguineous Indian families. Using a whole-genome linkage scan in one family, we identified a likely locus for microspherophakia (MSP1) on chromosome 14q24.1–q32.12 between markers D14S588 and D14S1050 in a physical distance of 22.76 Mb. The maximum multi-point lod score was 2.91 between markers D14S1020 and D14S606. The MSP1 candidate region harbors 110 reference genes. DNA sequence analysis of one of the genes, LTBP2, detected a homozygous duplication (insertion) mutation, c.5446dupC, in the last exon (exon 36) in affected family members. This homozygous mutation is predicted to elongate the LTBP2 protein by replacing the last 6 amino acids with 27 novel amino acids. Microspherophakia in the second family did not map to this locus, suggesting genetic heterogeneity. The present study suggests a role for LTBP2 in the structural stability of ciliary zonules, and growth and development of lens.