Hyperphosphatasia with mental retardation syndrome 3 (HPMRS3)

(OMIM phenotype number #614207)

Hyperphosphatasia with mental retardation syndrome 3 (HPRMS3) is a rare autosomal recessive form of HPRMS  (see also HPMRS1). This disease is caused by homozygous or compound heterozygous mutation in the PGAP2 gene. PGAP2 encodes a protein involved in fatty-acid glycosylphosphatidylinositol (GPI)-anchor remodeling, which occurs in the Golgi apparatus. It is required for stable association between GPI-anchored proteins (GPI-APs) and the cell-surface membrane rafts. Patients with PGAP2 mutations have secondary reduced GPI-AP surface levels also as a result of increased secretion into the extracellular space, resulting in high serum alkaline phosphatase (ALP). Germline mutations in six genes (PIGA, PIGL, PIGM, PIGV, PIGN, and PIGO) in the ER-located part of the GPI-anchor-biosynthesis pathway have been described. All these mutations are associated with phenotypes extending from malformation and lethality to severe intellectual disability, epilepsy, minor dysmorphisms, and high levels of ALP.

Gene

PGAP2 gene, 11p15.4 (OMIM gene/locus number #615187)

Phenotype

Delayed psychomotor development, severe mental retardation, intellectual disability mild (in some patients), hypotonia, seizures, disorder in sleep pattern (in some patients), cerebral atrophy (in some patients), microcephaly (in some patients), and cerebral atrophy (in some patients).

Main biochemical alterations

High ALP, high Pi, normal Ca, markedly high ALP, high acid phosphatase, high uric acid. 

Images

Hyperphosphatasia with mental retardation syndrome 3 (HPMRS3)

Fig. Phenotypic features of HPMRS3 (a and b). Face of a patient at the ages of 3 (a) and 28 years (b). (c) Normal-appearing fingernails of a patient. (d and e) Facial dysmorphism of a patient with HPMRS3 at the age of 2 years includes wide palpebral fissures, a short nose with a broad nasal bridge, a tented upper lip, and a small jaw. (f) Distal tapering of fingers and mild nail hypoplasia of the fifth digit of a patient with HPMRS3. 

 

Reproduced from Am J Hum Genet, Vol 92, Krawitz PM, Murakami Y, Rieß A, et al. PGAP2 mutations, affecting the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation syndrome, Pages 584-9, Copyright 2013, with permission from Elsevier.

References
  1. Krawitz PM, Murakami Y, Rieß A, et al. PGAP2 mutations, affecting the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation syndrome. Am J Hum Genet. 2013 Apr 4;92(4):584-9.
  2. Hansen L, Tawamie H, Murakami Y, et al. Hypomorphic mutations in PGAP2, encoding a GPI-anchor-remodeling protein, cause autosomal-recessive intellectual disability. Am J Hum Genet. 2013 Apr 4;92(4):575-83.
  3. Tashima Y, Taguchi R, Murata C, et al. PGAP2 is essential for correct processing and stable expression of GPI-anchored proteins. Mol Biol Cell. 2006 Mar;17(3):1410-20.
  4. Masi L, Agnusdei D, Bilezikian J et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015 Jun 13.
  5. http://www.omim.org