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Adult hypophosphatasia with a novel ALPL mutation: Report of an Indian kindred.

ABSTRACT: Hypophosphatasia is an inborn error in metabolism characterized by low serum alkaline phosphatase (ALP) activity resulting from deactivating mutations in TNSALP (also known as ALPL), the gene that encodes the 'tissue-specific' isoenzyme of ALP. The disease exhibits significant clinical heterogeneity that spans from death in utero to only dental complications in adult life. Herein, we report a 47-year-old woman presenting with fracture of shaft of left femur. She had been complaining of pain in both of her thighs for the past 3 years. In addition, she gave a history of premature loss of teeth. Review of old radiographs revealed pseudo-fractures involving the lateral cortices of the femora on both sides. Biochemical panel revealed hyperphosphatemia, persistently low total alkaline phosphatase (ALP) and low-normal bone turnover markers. Screening of her siblings revealed low ALP in her younger sister and brother who were otherwise free from any major dento-arthro-osseous complaints. Sanger sequencing showed a novel, heterozygous, missense mutation in exon 5 at position 311 (c.311a > g;p.104 Asn > Ser) of ALPL gene in the three members. The patient underwent open reduction and intramedullary nailing of left femur along with prophylactic nailing on right side. This case report represents the first genetically confirmed kindred of adult hypophosphatasia from the Indian subcontinent.

SUBMITTER: Bhadada SK

PROVIDER: S-EPMC6997823 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Adult hypophosphatasia with a novel ALPL mutation: Report of an Indian kindred.

Bhadada Sanjay K SK Pal Rimesh R Dhiman Vandana V Alonso Nerea N Ralston Stuart H SH Kaur Simran S Gupta Rajat R

Bone reports 20200124

Hypophosphatasia is an inborn error in metabolism characterized by low serum alkaline phosphatase (ALP) activity resulting from deactivating mutations in TNSALP (also known as ALPL), the gene that encodes the 'tissue-specific' isoenzyme of ALP. The disease exhibits significant clinical heterogeneity that spans from death in utero to only dental complications in adult life. Herein, we report a 47-year-old woman presenting with fracture of shaft of left femur. She had been com ...[more]

PMID: 32025537

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Project description:Loss-of-function mutations in ALPL result in hypophosphatasia (HPP), an inborn error of metabolism that causes defective skeletal and dental mineralization. ALPL encodes tissue-nonspecific alkaline phosphatase, an enzyme expressed in bone, teeth, liver, and kidney that hydrolyzes the mineralization inhibitor inorganic pyrophosphate. As Alpl-null mice die before weaning, we aimed to generate mouse models of late-onset HPP with extended life spans by engineering a floxed Alpl allele, allowing for conditional gene ablation (conditional knockout [cKO]) when crossed with Cre recombinase transgenic mice. The authors hypothesized that targeted deletion of Alpl in osteoblasts and selected dental cells ( Col1a1-cKO) or deletion in chondrocytes, osteoblasts, and craniofacial mesenchyme ( Prx1-cKO) would phenocopy skeletal and dental manifestations of late-onset HPP. Col1a1-cKO and Prx1-cKO mice were viable and fertile, and they did not manifest the epileptic seizures characteristic of the Alpl-/- model of severe infantile HPP. Both cKO models featured normal postnatal body weight but significant reduction as compared with wild type mice by 8 to 12 wk. Plasma alkaline phosphatase for both cKO models at 24 wk was reduced by approximately 75% as compared with controls. Radiography revealed profound skeletal defects in cKO mice, including rachitic changes, hypomineralized long bones, deformations, and signs of fractures. Microcomputed tomography confirmed quantitative differences in cortical and trabecular bone, including decreased cortical thickness and mineral density. Col1a1-cKO mice exhibited classic signs of HPP dentoalveolar disease, including short molar roots with thin dentin, lack of acellular cementum, and osteoid accumulation in alveolar bone. Prx1-cKO mice exhibited the same array of periodontal defects but featured less affected molar dentin. Both cKO models exhibited reduced alveolar bone height and 4-fold increased numbers of osteoclast-like cells versus wild type at 24 wk, consistent with HPP-associated periodontal disease. These novel models of late-onset HPP can inform on long-term skeletal and dental manifestations and will provide essential tools to further studies of etiopathologies and therapeutic interventions.

Project description:IntroductionHypophosphatasia (HPP) is an inborn metabolic error caused by mutations in the ALPL gene encoding tissue non-specific alkaline phosphatase (TNSALP) and leading to decreased alkaline phosphatase (ALP) activity. Although the main characteristic of this disease is bone involvement, it presents a great genetic and clinical variability, which makes it a systemic disease.MethodsPatients were recruited based on biochemical assessments. Diagnosis was made by measuring serum ALP and pyridoxal 5-phosphate levels and finally by Sanger sequencing of the ALPL gene from peripheral blood mononuclear cells. Characterization of the new variants was performed by transfection of the variants into HEK293T cells, where ALP activity and cellular localization were measured by flow cytometry. The dominant negative effect was analyzed by co-transfection of each variant with the wild-type gene, measuring ALP activity and analyzing cellular localization by flow cytometry.ResultsTwo previously undescribed variants were found in the ALPL gene: leucine 6 to serine missense mutation (c.17T>C, L6S) affecting the signal peptide and threonine 167 deletion (c.498_500delCAC, T167del) affecting the vicinity of the active site. These mutations lead mainly to non-pathognomonic symptoms of HPP. Structural prediction and modeling tools indicated the affected residues as critical residues with important roles in protein structure and function. In vitro results demonstrated low TNSALP activity and a dominant negative effect in both mutations. The results of the characterization of these variants suggest that the pleiotropic role of TNSALP could be involved in the systemic effects observed in these patients highlighting digestive and autoimmune disorders associated with TNSALP dysfunction.ConclusionsThe two new mutations have been classified as pathogenic. At the clinical level, this study suggests that both mutations not only lead to pathognomonic symptoms of the disease, but may also play a role at the systemic level.

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Adult hypophosphatasia with a novel ALPL mutation: Report of an Indian kindred.

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Adult hypophosphatasia with a novel <i>ALPL</i> mutation: Report of an Indian kindred.

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