Molecular Genetics of Hypophosphatasia and Phenotype-Genotype Correlations

Abstract

Hypophosphatasia (HPP) is due to deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNAP). This enzyme cleaves extracellular substrates inorganic pyrophosphates (PPi), pyridoxal-5'-phosphate (PLP), phosphoethanolamine (PEA) and nucleotides, and probably other substrates not yet identified. During the last 15 years the role of TNAP in mineralization, and to a less degree in brain, has been investigated, providing hypotheses and explanations for both bone and neuronal HPP phenotypes. ALPL, the gene encoding TNAP, is subject to many mutations, mostly missense mutations. A few number of mutations are recurrently found and may be quite frequent in particular populations. This reflects founder effects. The great variety of mutations results in a great number of compound heterozygous genotypes and in highly variable clinical expressivity. A good correlation was observed between the severity of the disease and in vitro enzymatic activity of the mutant protein measured after site-directed mutagenesis. Many missense mutations found in severe hypophosphatasia produced a mutant protein that failed to reach the cell membrane , was accumulated in the cis-Golgi and was subsequently degraded in the proteasome. Missense mutations located in the catalytic site or in the homodimer interface were often shown by site-directed mutagenesis to have a dominant negative effect. Currently molecular diagnosis of HPP is based on the sequencing of the coding sequence of ALPL that allows detection of approximately 95 % of mutations in severe cases. In addition, other genes, especially genes encoding proteins involved in the regulation of extracellular PPi concentration, could modify the phenotype (modifier genes).

Molecular and clinical analysis of ALPL in a cohort of patients with suspicion of Hypophosphatasia

“…The incidence of the severe forms of this disease is estimated to be approximately 1 in 300,000 in European populations and 1 in 100,000 in Canadian population, probably due a founder effect in the Mennonite Canadian population [Fraser, ; Greenberg et al, ; Mornet et al, ; Leung et al, ] and very rare in black populations [Whyte, ]. The prevalence of the mild forms, those that do not compromise survival and whose symptoms appear in the childhood has been estimated at 1/6,000 [Mornet, ].…”

Hypophosphatasia: Review of Bone Mineral Metabolism, Pathophysiology, Clinical Presentation, Diagnosis, and Treatment

“…Greater than 300 ALPL gene mutations have been identified and are reported in the ALPL gene mutation database (http://www.sesep.uvsq.fr/03_hypo_ mutations.php). Molecular testing of the ALPL gene identifies multiple genotypes with variable expressivity [18,19]. About 80 % of the known mutations are missense point mutations, 10 % are small deletions, 4 % splicing mutations, 3 % nonsense mutations, 2 % small insertions, and ≤1 % complex insertion/deletions, large deletions, or mutations in the regulatory sequence [17,19,20].…”

Hypophosphatasie – eine klinisch und genetisch variable Erkrankung

“…Zwei Fälle einer HPP infolge einer uniparentalen Isodisomie sind beschrieben [16,17]. Ein Founder-Effekt ist für spezifische Mutationen in manchen Populationen beschrieben [18].…”