ALPL – Hypophosphatasia

Hypophosphatasia is an autosomal recessive metabolic bone disease caused by biallelic loss-of-function mutations in the tissue-nonspecific alkaline phosphatase gene (ALPL). A landmark multi-family study first identified eight distinct ALPL missense alleles in 23 unrelated patients with perinatal/infantile or severe forms of hypophosphatasia, each absent from ≥63 controls, confirming recessive inheritance and broad allelic heterogeneity (PMID:1409720).

Genetic evidence includes over 150 pathogenic ALPL variants reported across diverse populations, spanning missense (>100), nonsense (>10), splice site (>10), and frameshift (>20) classes. Compound heterozygotes predominate in perinatal and infantile forms, while some mild and adult cases exhibit dominant-negative or haploinsufficient alleles (PMID:15671102). Segregation of recessive alleles in at least 23 families supports a definitive gene–disease relationship.

Founder effects are well documented: the E174K missense allele accounts for ~31% of Caucasian mild HPP chromosomes on a shared haplotype (PMID:12357339), while the Japanese-specific c.1559del founder mutation comprises up to 36% of disease alleles and a carrier frequency of ~1/480 in that population (PMID:11810413; PMID:21179104).

Functional assays demonstrate that many ALPL mutants fail to traffic to the cell surface, aggregate intracellularly, or undergo proteasomal degradation, resulting in absent or severely reduced enzyme activity. The c.1559del (p.Leu520ArgfsTer?) frameshift mutation, for example, forms disulfide-linked aggregates lacking membrane anchoring, fully explaining lethal perinatal phenotypes (PMID:15794757). Other missense alleles show differential residual activity, correlating with clinical severity.

Clinical heterogeneity spans lethal perinatal forms presenting with pulmonary hypoplasia and seizures, to mild adult-onset cases with recurrent fractures, osteomalacia, dental premature tooth loss, rickets (HP:0002748), and muscle weakness. Enzyme replacement therapy with asfotase alfa can rescue bone and neurologic manifestations when initiated early.

No substantive conflicting studies dispute ALPL’s causative role; however, heterozygous carriers may exhibit subclinical biochemical abnormalities without overt disease. Modifier effects and variable expressivity underscore the need for comprehensive genetic and biochemical evaluation in individuals with low alkaline phosphatase.

Key Take-home: ALPL mutations cause hypophosphatasia through enzyme deficiency and defective bone mineralization; genetic testing and functional assays guide diagnosis, prognostic stratification, and enable timely enzyme replacement therapy.

References

• Proceedings of the National Academy of Sciences of the United States of America • 1992 • Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia. PMID:1409720
• The Journal of Clinical Endocrinology and Metabolism • 2005 • Childhood hypophosphatasia due to a de novo missense mutation in the tissue-nonspecific alkaline phosphatase gene. PMID:15671102
• European Journal of Human Genetics • 2002 • Evidence of a founder effect for the tissue-nonspecific alkaline phosphatase (TNSALP) gene E174K mutation in hypophosphatasia patients. PMID:12357339
• Journal of Bone and Mineral Metabolism • 2002 • Importance of deletion of T at nucleotide 1559 in the tissue-nonspecific alkaline phosphatase gene in Japanese patients with hypophosphatasia. PMID:11810413
• Journal of Human Genetics • 2011 • Prevalence of c.1559delT in ALPL, a common mutation resulting in the perinatal (lethal) form of hypophosphatasia in Japanese and effects of the mutation on heterozygous carriers. PMID:21179104
• The FEBS Journal • 2005 • Novel aggregate formation of a frame-shift mutant protein of tissue-nonspecific alkaline phosphatase is ascribed to three cysteine residues in the C-terminal extension. PMID:15794757

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