A homozygous missense variant in the alkaline phosphatase gene ALPL is associated with a severe form of canine hypophosphatasia

Kyöstilä, Kaisa; Syrjä, Pernilla; Lappalainen, Anu K.; Arumilli, Meharji; Hundi, Sruthi; Karkamo, Veera; Viitmaa, Ranno; Hytönen, Marjo K.; Lohi, Hannes

doi:10.1038/s41598-018-37801-2

Cited by 8 publications

(4 citation statements)

References 73 publications

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“…A previous report described a naturally occurring autosomal recessive mutation (c.1301T>G; p.V434G) in Karelian Bear Dogs in Finland. ( 42 ) Affected dogs exhibited early lethality, altered craniofacial shape, severe rickets, and osteomalacia. The authors reported normal appearance of teeth by histology and did not note premature tooth loss.…”

Section: Discussionmentioning

confidence: 99%

Dentoalveolar Defects of Hypophosphatasia are Recapitulated in a Sheep Knock-In Model

Mohamed

Chavez

Huggins

et al. 2020

Journal of Bone and Mineral Research

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Hypophosphatasia (HPP) is the inherited error-of-metabolism caused by mutations in ALPL, reducing the function of tissuenonspecific alkaline phosphatase (TNAP/TNALP/TNSALP). HPP is characterized by defective skeletal and dental mineralization and is categorized into several clinical subtypes based on age of onset and severity of manifestations, though premature tooth loss from acellular cementum defects is common across most HPP subtypes. Genotype-phenotype associations and mechanisms underlying musculoskeletal, dental, and other defects remain poorly characterized. Murine models that have provided significant insights into HPP pathophysiology also carry limitations including monophyodont dentition, lack of osteonal remodeling of cortical bone, and differing patterns of skeletal growth. To address this, we generated the first gene-edited large-animal model of HPP in sheep via CRISPR/Cas9-mediated knock-in of a missense mutation (c.1077C>G; p.I359M) associated with skeletal and dental manifestations in humans. We hypothesized that this HPP sheep model would recapitulate the human dentoalveolar manifestations of HPP. Compared to wild-type (WT), compound heterozygous (cHet) sheep with one null allele and the other with the targeted mutant allele exhibited the most severe alveolar bone, acellular cementum, and dentin hypomineralization defects. Sheep homozygous for the mutant allele (Hom) showed alveolar bone and hypomineralization effects and trends in dentin and cementum, whereas sheep heterozygous (Het) for the mutation did not exhibit significant effects. Important insights gained include existence of early alveolar bone defects that may contribute to tooth loss in HPP, observation of severe mantle dentin hypomineralization in an HPP animal model, association of cementum hypoplasia with genotype, and correlation of dentoalveolar defects with alkaline phosphatase (ALP) levels. The sheep model of HPP faithfully recapitulated dentoalveolar defects reported in individuals with HPP, providing a new translational model for studies into etiopathology and novel therapies of this disorder, as well as proof-of-principle that genetically engineered large sheep models can replicate human dentoalveolar disorders.

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Section: Discussionmentioning

confidence: 99%

Dentoalveolar Defects of Hypophosphatasia are Recapitulated in a Sheep Knock-In Model

Mohamed

Chavez

Huggins

et al. 2020

Journal of Bone and Mineral Research

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“…The sample for the dam of the litter was not available, but the sire was tested as a carrier. Of note, as the clinical presentation of these two puppies resembled a previously recognized genetic condition occurring in the breed, hypophosphatasia (Kyöstila et al 2019), the puppies were also tested for the hypophosphatasia-associated ALPL gene variant. Both puppies were homozygous wildtype for the ALPL variant, ruling out this condition.…”

Section: Segregation Breed Specificity and The Carrier Frequency Of mentioning

confidence: 99%

Intronic variant in POU1F1 associated with canine pituitary dwarfism

et al. 2021

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The anterior pituitary gland secretes several endocrine hormones, essential for growth, reproduction and other basic physiological functions. Abnormal development or function of the pituitary gland leads to isolated or combined pituitary hormone deficiency (CPHD). At least 30 genes have been associated with human CPHD, including many transcription factors, such as POU1F1. CPHD occurs spontaneously also in mice and dogs. Two affected breeds have been reported in dogs: German Shepherds with a splice defect in the LHX3 gene and Karelian Bear Dogs (KBD) with an unknown genetic cause. We obtained samples from five KBDs presenting dwarfism and abnormal coats. A combined analysis of genome-wide association and next-generation sequencing mapped the disease to a region in chromosome 31 and identified a homozygous intronic variant in the fourth exon of the POU1F1 gene in the affected dogs. The identified variant, c.605-3C>A, resided in the splice region and was predicted to affect splicing. The variant's screening in three new prospective cases, related breeds, and ~ 8000 dogs from 207 breeds indicated complete segregation in KBDs with a carrier frequency of 8%, and high breed-specificity as carriers were found at a low frequency only in Lapponian Herders, a related breed. Our study establishes a novel canine model for CPHD with a candidate POU1F1 defect.

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“…The ALPL gene is localized on chromosome 1p36.1–34 and consists of 12 exons distributed over 50 kb [ 9 , 10 ], ALPL mutation detection is important for recurrence risk assessment and prenatal diagnosis [ 11 ]. To date, more than 400 ALPL gene mutations have been reported worldwide and approximately 80% of these mutations are missense.…”

Section: Introductionmentioning

confidence: 99%

Dissecting mutational allosteric effects in alkaline phosphatases associated with different Hypophosphatasia phenotypes: An integrative computational investigation

Xiao

Zhou²,

Song³

et al. 2022

PLoS Comput Biol

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Hypophosphatasia (HPP) is a rare inherited disorder characterized by defective bone mineralization and is highly variable in its clinical phenotype. The disease occurs due to various loss-of-function mutations in ALPL, the gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). In this work, a data-driven and biophysics-based approach is proposed for the large-scale analysis of ALPL mutations-from nonpathogenic to severe HPPs. By using a pipeline of synergistic approaches including sequence-structure analysis, network modeling, elastic network models and atomistic simulations, we characterized allosteric signatures and effects of the ALPL mutations on protein dynamics and function. Statistical analysis of molecular features computed for the ALPL mutations showed a significant difference between the control, mild and severe HPP phenotypes. Molecular dynamics simulations coupled with protein structure network analysis were employed to analyze the effect of single-residue variation on conformational dynamics of TNSALP dimers, and the developed machine learning model suggested that the topological network parameters could serve as a robust indicator of severe mutations. The results indicated that the severity of disease-associated mutations is often linked with mutation-induced modulation of allosteric communications in the protein. This study suggested that ALPL mutations associated with mild and more severe HPPs can exert markedly distinct effects on the protein stability and long-range network communications. By linking the disease phenotypes with dynamic and allosteric molecular signatures, the proposed integrative computational approach enabled to characterize and quantify the allosteric effects of ALPL mutations and role of allostery in the pathogenesis of HPPs.

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A homozygous missense variant in the alkaline phosphatase gene ALPL is associated with a severe form of canine hypophosphatasia

Cited by 8 publications

References 73 publications

Dentoalveolar Defects of Hypophosphatasia are Recapitulated in a Sheep Knock-In Model

Dentoalveolar Defects of Hypophosphatasia are Recapitulated in a Sheep Knock-In Model

Intronic variant in POU1F1 associated with canine pituitary dwarfism

Dissecting mutational allosteric effects in alkaline phosphatases associated with different Hypophosphatasia phenotypes: An integrative computational investigation

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