Autosomal-recessive posterior microphthalmos is caused by mutations in PRSS56, a gene encoding a trypsin-like serine protease

Andreas Gal; Isabella Rau; Leila El Matri; Hans-Jürgen Kreienkamp; Susanne Fehr; Karim Baklouti; Ibtissem Chouchane; Yun Li; Monika Rehbein; Josefine Fuchs; Hans C Fledelius; Kaj Vilhelmsen; Daniel F Schorderet; Francis L Munier; Elsebet Ostergaard; Debra A Thompson; Thomas Rosenberg

doi:http://dx.doi.org/10.1016/j.ajhg.2011.02.006

Autosomal-recessive posterior microphthalmos is caused by mutations in PRSS56, a gene encoding a trypsin-like serine protease

Andreas Gal, Isabella Rau, Leila El Matri, Hans-Jürgen Kreienkamp, Susanne Fehr, Karim Baklouti, Ibtissem Chouchane, Yun Li, Monika Rehbein, Josefine Fuchs, Hans C Fledelius, Kaj Vilhelmsen, Daniel F Schorderet, Francis L Munier, Elsebet Ostergaard, Debra A Thompson, Thomas Rosenberg

53 Citationer (Scopus)

Abstract

Posterior microphthalmos (MCOP) is a rare isolated developmental anomaly of the eye characterized by extreme hyperopia due to short axial length. The population of the Faroe Islands shows a high prevalence of an autosomal-recessive form (arMCOP) of the disease. Based on published linkage data, we refined the position of the disease locus (MCOP6) in an interval of 250 kb in chromosome 2q37.1 in two large Faroese families. We detected three different mutations in PRSS56. Patients of the Faroese families were either homozygous for c.926G>C (p.Trp309Ser) or compound heterozygous for c.926G>C and c.526C>G (p.Arg176Gly), whereas a homozygous 1 bp duplication (c.1066dupC) was identified in five patients with arMCOP from a consanguineous Tunisian family. In one patient with MCOP from the Faroe Islands and in another one from Turkey, no PRSS56 mutation was detected, suggesting nonallelic heterogeneity of the trait. Using RT-PCR, PRSS56 transcripts were detected in samples derived from the human adult retina, cornea, sclera, and optic nerve. The expression of the mouse ortholog could be first detected in the eye at E17 and was maintained into adulthood. The predicted PRSS56 protein is a 603 amino acid long secreted trypsin-like serine peptidase. The c.1066dupC is likely to result in a functional null allele, whereas the two point mutations predict the replacement of evolutionary conserved and functionally important residues. Molecular modeling of the p.Trp309Ser mutant suggests that both the affinity and reactivity of the enzyme toward in vivo protein substrates are likely to be substantially reduced.

Originalsprog	Engelsk
Tidsskrift	American Journal of Human Genetics
Vol/bind	88
Udgave nummer	3
Sider (fra-til)	382-90
Antal sider	9
ISSN	0002-9297
DOI	https://doi.org/10.1016/j.ajhg.2011.02.006
Status	Udgivet - 11 mar. 2011

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http://dx.doi.org/10.1016/j.ajhg.2011.02.006

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Gal, A., Rau, I., El Matri, L., Kreienkamp, H-J., Fehr, S., Baklouti, K., Chouchane, I., Li, Y., Rehbein, M., Fuchs, J., Fledelius, H. C., Vilhelmsen, K., Schorderet, D. F., Munier, F. L., Ostergaard, E., Thompson, D. A., & Rosenberg, T. (2011). Autosomal-recessive posterior microphthalmos is caused by mutations in PRSS56, a gene encoding a trypsin-like serine protease. American Journal of Human Genetics, 88(3), 382-90. https://doi.org/10.1016/j.ajhg.2011.02.006

Gal, A, Rau, I, El Matri, L, Kreienkamp, H-J, Fehr, S, Baklouti, K, Chouchane, I, Li, Y, Rehbein, M, Fuchs, J, Fledelius, HC, Vilhelmsen, K, Schorderet, DF, Munier, FL, Ostergaard, E, Thompson, DA & Rosenberg, T 2011, 'Autosomal-recessive posterior microphthalmos is caused by mutations in PRSS56, a gene encoding a trypsin-like serine protease', American Journal of Human Genetics, bind 88, nr. 3, s. 382-90. https://doi.org/10.1016/j.ajhg.2011.02.006

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title = "Autosomal-recessive posterior microphthalmos is caused by mutations in PRSS56, a gene encoding a trypsin-like serine protease",

abstract = "Posterior microphthalmos (MCOP) is a rare isolated developmental anomaly of the eye characterized by extreme hyperopia due to short axial length. The population of the Faroe Islands shows a high prevalence of an autosomal-recessive form (arMCOP) of the disease. Based on published linkage data, we refined the position of the disease locus (MCOP6) in an interval of 250 kb in chromosome 2q37.1 in two large Faroese families. We detected three different mutations in PRSS56. Patients of the Faroese families were either homozygous for c.926G>C (p.Trp309Ser) or compound heterozygous for c.926G>C and c.526C>G (p.Arg176Gly), whereas a homozygous 1 bp duplication (c.1066dupC) was identified in five patients with arMCOP from a consanguineous Tunisian family. In one patient with MCOP from the Faroe Islands and in another one from Turkey, no PRSS56 mutation was detected, suggesting nonallelic heterogeneity of the trait. Using RT-PCR, PRSS56 transcripts were detected in samples derived from the human adult retina, cornea, sclera, and optic nerve. The expression of the mouse ortholog could be first detected in the eye at E17 and was maintained into adulthood. The predicted PRSS56 protein is a 603 amino acid long secreted trypsin-like serine peptidase. The c.1066dupC is likely to result in a functional null allele, whereas the two point mutations predict the replacement of evolutionary conserved and functionally important residues. Molecular modeling of the p.Trp309Ser mutant suggests that both the affinity and reactivity of the enzyme toward in vivo protein substrates are likely to be substantially reduced.",

author = "Andreas Gal and Isabella Rau and {El Matri}, Leila and Hans-J{\"u}rgen Kreienkamp and Susanne Fehr and Karim Baklouti and Ibtissem Chouchane and Yun Li and Monika Rehbein and Josefine Fuchs and Fledelius, {Hans C} and Kaj Vilhelmsen and Schorderet, {Daniel F} and Munier, {Francis L} and Elsebet Ostergaard and Thompson, {Debra A} and Thomas Rosenberg",

year = "2011",

month = mar,

day = "11",

doi = "http://dx.doi.org/10.1016/j.ajhg.2011.02.006",

language = "English",

volume = "88",

pages = "382--90",

journal = "American Journal of Human Genetics",

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TY - JOUR

T1 - Autosomal-recessive posterior microphthalmos is caused by mutations in PRSS56, a gene encoding a trypsin-like serine protease

AU - Gal, Andreas

AU - Rau, Isabella

AU - El Matri, Leila

AU - Kreienkamp, Hans-Jürgen

AU - Fehr, Susanne

AU - Baklouti, Karim

AU - Chouchane, Ibtissem

AU - Li, Yun

AU - Rehbein, Monika

AU - Fuchs, Josefine

AU - Fledelius, Hans C

AU - Vilhelmsen, Kaj

AU - Schorderet, Daniel F

AU - Munier, Francis L

AU - Ostergaard, Elsebet

AU - Thompson, Debra A

AU - Rosenberg, Thomas

PY - 2011/3/11

Y1 - 2011/3/11

N2 - Posterior microphthalmos (MCOP) is a rare isolated developmental anomaly of the eye characterized by extreme hyperopia due to short axial length. The population of the Faroe Islands shows a high prevalence of an autosomal-recessive form (arMCOP) of the disease. Based on published linkage data, we refined the position of the disease locus (MCOP6) in an interval of 250 kb in chromosome 2q37.1 in two large Faroese families. We detected three different mutations in PRSS56. Patients of the Faroese families were either homozygous for c.926G>C (p.Trp309Ser) or compound heterozygous for c.926G>C and c.526C>G (p.Arg176Gly), whereas a homozygous 1 bp duplication (c.1066dupC) was identified in five patients with arMCOP from a consanguineous Tunisian family. In one patient with MCOP from the Faroe Islands and in another one from Turkey, no PRSS56 mutation was detected, suggesting nonallelic heterogeneity of the trait. Using RT-PCR, PRSS56 transcripts were detected in samples derived from the human adult retina, cornea, sclera, and optic nerve. The expression of the mouse ortholog could be first detected in the eye at E17 and was maintained into adulthood. The predicted PRSS56 protein is a 603 amino acid long secreted trypsin-like serine peptidase. The c.1066dupC is likely to result in a functional null allele, whereas the two point mutations predict the replacement of evolutionary conserved and functionally important residues. Molecular modeling of the p.Trp309Ser mutant suggests that both the affinity and reactivity of the enzyme toward in vivo protein substrates are likely to be substantially reduced.

AB - Posterior microphthalmos (MCOP) is a rare isolated developmental anomaly of the eye characterized by extreme hyperopia due to short axial length. The population of the Faroe Islands shows a high prevalence of an autosomal-recessive form (arMCOP) of the disease. Based on published linkage data, we refined the position of the disease locus (MCOP6) in an interval of 250 kb in chromosome 2q37.1 in two large Faroese families. We detected three different mutations in PRSS56. Patients of the Faroese families were either homozygous for c.926G>C (p.Trp309Ser) or compound heterozygous for c.926G>C and c.526C>G (p.Arg176Gly), whereas a homozygous 1 bp duplication (c.1066dupC) was identified in five patients with arMCOP from a consanguineous Tunisian family. In one patient with MCOP from the Faroe Islands and in another one from Turkey, no PRSS56 mutation was detected, suggesting nonallelic heterogeneity of the trait. Using RT-PCR, PRSS56 transcripts were detected in samples derived from the human adult retina, cornea, sclera, and optic nerve. The expression of the mouse ortholog could be first detected in the eye at E17 and was maintained into adulthood. The predicted PRSS56 protein is a 603 amino acid long secreted trypsin-like serine peptidase. The c.1066dupC is likely to result in a functional null allele, whereas the two point mutations predict the replacement of evolutionary conserved and functionally important residues. Molecular modeling of the p.Trp309Ser mutant suggests that both the affinity and reactivity of the enzyme toward in vivo protein substrates are likely to be substantially reduced.

U2 - http://dx.doi.org/10.1016/j.ajhg.2011.02.006

DO - http://dx.doi.org/10.1016/j.ajhg.2011.02.006

M3 - Journal article

SN - 0002-9297

VL - 88

SP - 382

EP - 390

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 3

ER -

Autosomal-recessive posterior microphthalmos is caused by mutations in PRSS56, a gene encoding a trypsin-like serine protease

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