A novel MGP mutation in a consanguineous family: Review of the clinical and molecular characteristics of Keutel syndrome

Abstract

Keutel syndrome (KS) [OMIM 245150] is a rare autosomal recessive condition, characterized by abnormal cartilage calcification. Mutations in the matrix Gla protein gene (MGP) have been previously reported in three unrelated KS families. MGP is an extracellular matrix protein that acts as a calcification inhibitor by repressing bone morphogenetic protein 2 (BMP2). Loss-of-function mutations of MGP result in abnormal calcification of the soft tissues, a cardinal feature of KS. We report the fourth MGP mutation (IVS2 + 1G > A) in a consanguineous Arab family, which results in the loss of the consensus donor splice site at the exon 2-intron 2 junction. In addition to the typical manifestations, we observed abnormalities in the white matter of the brain, optic nerve atrophy, and mid-dermal elastolysis in the affected individuals of this family. This report broadens the clinical phenotype observed in patients with KS. The effect of the IVS2 + 1G > A mutation is consistent with the previously reported loss-of-function mutations of MGP.

Gla-Rich Protein Is a Novel Vitamin K-Dependent Protein Present in Serum That Accumulates at Sites of Pathological Calcifications

“…However, a new variant of Keutel syndrome characterized by a new MGP mutation recently identified in a consanguineous family, showed overlapping features of cutis laxa. 37 Whether loss of MGP function can explain all of the clinical manifestations observed within these patients, in particular the skin alterations, was further discussed and questioned, and other possibilities such as additional unidentified mutations in other genes were suggested. 16 Besides skin, we found GRP highly accumulated in small and medium size blood vessels in rat, and we were able to confirm its presence in the human vascular system, both by immunohistochemistry and Western blot.…”

Unfoldomics of Human Genetic Diseases: Illustrative Examples of Ordered and Intrinsically Disordered Members of the Human Diseasome

“…Keutel syndrome (characterized by diffuse cartilage calcification, characteristic physiognomy, brachytelephalangism, peripheral pulmonary stenosis, hearing loss, and borderline to mild mental retardation) is caused by the mutations in the matrix Gla protein gene (MGP) encoding an extracellular matrix protein MGP that acts as a calcification inhibitor by repressing bone morphogenetic protein 2. Loss-of-function mutations of MGP result in abnormal calcification of the soft tissues [132]. Limb-mammary syndrome is characterized by splithand-split-foot malformation (ectrodactyly) and aplasia or hypoplasia of the mammary gland and nipple.…”

Osteopontin Upregulation and Polymerization by Transglutaminase 2 in Calcified Arteries of Matrix Gla Protein-deficient Mice

“…This pathological mineralization process differs from that found in atherosclerosis and involves increased vessel rigidity and thickness without loss of arterial lumen patency (Proudfoot and Shanahan 2001). Vascular calcification decreases elasticity of the blood vessels and increases their brittleness, leading to increased risk of arterial rupture (Hur et al 2005).…”