ALPL – perinatal lethal hypophosphatasia

ALPL encodes tissue-nonspecific alkaline phosphatase (TNSALP), a GPI-anchored enzyme essential for skeletal mineralization. Biallelic pathogenic variants in ALPL cause perinatal lethal hypophosphatasia, characterized by severe osteochondral hypomineralization, intrauterine fractures, and limb hypoplasia.

Autosomal recessive inheritance is supported by compound heterozygous mutations identified in unrelated fetuses. In a stillborn fetus at 22 weeks with limb shortening and aplasia of the extremities, targeted NGS of 2741 Mendelian genes revealed c.1283G>C (p.Arg428Pro) and c.1363G>A (p.Gly455Ser) in trans (PMID:27179278). A separate 22+4-week gestation fetus exhibited c.648+1G>A (donor splice) and c.1250A>G (p.Asn417Ser) transmitted from unaffected heterozygous parents (PMID:11745997). Both reports showed no additional affected relatives, consistent with recessive segregation.

Mechanistically, pathogenic ALPL variants result in TNSALP misfolding, impaired GPI-anchor processing, Golgi retention, disulfide-linked aggregates, proteasome-mediated degradation, and deficient phosphatase activity. Functional assays across >20 missense, splice, and frameshift alleles demonstrate near-absent enzyme activity and failure to localize to the cell surface, confirming loss-of-function as the disease mechanism.

Integration of genetic and experimental data establishes a definitive gene–disease relationship between ALPL and perinatal lethal hypophosphatasia. Early molecular diagnosis via ALPL sequencing or enzymatic assays enables accurate prenatal counseling, recurrence risk assessment, and informed perinatal management.

Key take-home: Molecular confirmation of ALPL variants is critical for the prenatal diagnosis and genetic counseling of perinatal lethal hypophosphatasia.

References

• Polish journal of pathology • 2016 • Identification of a molecular defect in a stillborn fetus with perinatal lethal hypophosphatasia using a disease-associated genome sequencing approach. PMID:27179278
• American journal of medical genetics • 2001 • Perinatal hypophosphatasia: radiology, pathology and molecular biology studies in a family harboring a splicing mutation (648+1A) and a novel missense mutation (N400S) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene. PMID:11745997

Evidence Based Scoring (AI generated)