MGP – Keutel syndrome

Keutel syndrome (KS) is a rare autosomal recessive disorder characterized by abnormal cartilage calcification, brachytelephalangism, peripheral pulmonary artery stenosis, midface retrusion and other skeletal and cardiovascular anomalies. Pathogenic variants in MGP, which encodes matrix Gla protein, disrupt vitamin K–dependent γ-carboxylation required for binding mineral ions, leading to ectopic calcification of cartilage and, in some cases, vascular tissues.

Genetic analysis in multiple cohorts identified biallelic loss-of-function variants in MGP in 28 patients from 18 families ([PMID:24458983]). Variant types include nonsense (e.g., c.87T>A (p.Tyr29Ter)), splice-site (c.94+2T>C), start-loss (c.2T>C (p.Met1Thr)), frameshift, and exon deletions, all predicted to abrogate MGP function.

Segregation analyses in consanguineous families confirm autosomal recessive inheritance, with three additional affected siblings carrying homozygous MGP variants in independent kindreds ([PMID:9916809]). Intrafamilial variability has been noted: two Turkish sisters homozygous for c.62-2A>G exhibited differential severity of cartilage calcification and midface retrusion ([PMID:26349188]), and a Brazilian patient with c.2T>C (p.Met1Thr) underscores the recurrent LoF spectrum ([PMID:29928182]).

Functional studies support haploinsufficiency as the principal mechanism: Mgp-/- mice display inappropriate cartilage calcification analogous to KS ([PMID:9916809]), and in vitro assays demonstrate that MGP deficiency increases matrix mineralization. Circulating MGP species analysis in KS patients revealed elevated phosphorylated and under-carboxylated MGP refractory to vitamin K treatment ([PMID:21435166]). Promoter analyses further refine the regulatory landscape of MGP expression ([PMID:11425864]).

No significant conflicting evidence has been reported; notably, human KS patients typically lack the severe arterial calcification seen in murine models. A recent review summarizes 50 years of genetic and mechanistic insights into MGP function and KS pathogenesis ([PMID:33996798]).

Together, genetic and experimental data fulfill ClinGen Strong criteria for pathogenicity, guiding diagnostic screening and management of suspected KS. Key Take-home: Biallelic MGP loss-of-function variants reliably predict Keutel syndrome, supporting early genetic testing for affected individuals.

References

• Nature Genetics • 1999 • Mutations in the gene encoding the human matrix Gla protein cause Keutel syndrome. PMID:9916809
• American Journal of Medical Genetics Part A • 2014 • Keutel syndrome: report of two novel MGP mutations and discussion of clinical overlap with arylsulfatase E deficiency and relapsing polychondritis. PMID:24458983
• Genetic Counseling (Geneva, Switzerland) • 2015 • Clinical variability in two sisters with Keutel syndrome due to a homozygous mutation in MGP gene. PMID:26349188
• Molecular Syndromology • 2018 • A Novel MGP Gene Mutation Causing Keutel Syndrome in a Brazilian Patient. PMID:29928182
• Journal of Thrombosis and Haemostasis • 2011 • Circulating matrix γ-carboxyglutamate protein (MGP) species are refractory to vitamin K treatment in a new case of Keutel syndrome. PMID:21435166
• The Journal of Biological Chemistry • 2001 • A polymorphism of the human matrix γ-carboxyglutamic acid protein promoter alters binding of an activating protein-1 complex and is associated with altered transcription and serum levels. PMID:11425864
• Frontiers in Cell and Developmental Biology • 2021 • Keutel Syndrome, a Review of 50 Years of Literature. PMID:33996798

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