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Archives de pédiatrie
Volume 24, n° 5S2
pages 551-556 (mai 2017)
Doi : 10.1016/S0929-693X(18)30014-9
Genetics of hypophosphatasia
Génétique de l’hypophosphatasie
 

E. Mornet
 Service de biologie, unité de génétique constitutionnelle, centre hospitalier de Versailles, Le Chesnay, France 

*Corresponding author.
Summary

Hypophosphatasia (HPP) is a rare inherited disorder primarily affecting bone and dental mineralization. Although there is a continuum in the severity of the disease, clinical forms may be arbitrarily distinguished on the basis of age at onset and the presence or absence of bone symptoms: perinatal, infantile, juvenile, adult, prenatal benign, and odontological. Severe forms (perinatal and infantile) are autosomally recessively inherited while less severe forms may be autosomally recessively or dominantly inherited. Genetic counseling is complicated by the coexistence of the two modes of inheritance, the incomplete penetrance of the dominant forms, the markedly variable expression of the disease, including intra-familial expression, and the existence of a benign prenatal form that may sometimes be difficult to distinguish from the severe prenatal form. The disease is due to loss-of-function mutations in the Alkaline Phosphatase-Liver (ALPL ) gene encoding the tissue nonspecific alkaline phosphatase (TNSALP). The great variety of missence mutations and the dominant negative effect of some mutations largely explain the clinical heterogeneity. Directed mutagenesis studies allowed further elucidation of the cellular pathophysiology of HPP, classification of the alleles in terms of their severity and dominant negative effect, and molecular explanations of the dominant inheritance mode. Genetics significantly contributed to show that there are in fact two HPPs, rare, severe and recessive HPP, and mild recessive or mild dominant HPP, which is markedly more frequent and probably under-diagnosed. The prevalence of the severe forms of HPP has been estimated to be 1/300,000 in France and Northern Europe while the prevalence of the moderate forms of HPP may reach 1/6,370.

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Résumé

L’hypophosphatasie (HPP) est une maladie héréditaire affectant essentiellement la minéralisation osseuse et dentaire. Bien qu’il existe un continuum dans la sévérité de l’affection, on distingue six formes cliniques en fonction de l’âge d’apparition des symptômes et de la présence ou non de manifestations osseuses : périnatale, infantile, juvénile, adulte, prénatale bénigne et odontologique. Les formes sévères (périnatale et infantile) sont transmises sur le mode récessif autosomique tandis que les formes moins sévères peuvent être transmises sur les modes dominant ou récessif autosomiques. Le conseil génétique est compliqué par la coexistence des deux modes de transmission, la pénétrance incomplète des formes dominantes, l’expressivité variable, y compris intrafamiliale, et l’existence d’une forme prénatale bénigne parfois difficile à distinguer de la forme prénatale sévère. La maladie est due aux mutations du gène Alkaline Phosphatase-Liver (ALPL ) codant pour la phosphatase alcaline non tissu-spécifique (TNSALP). La grande variété de mutations faux-sens ainsi que l’effet dominant négatif de certaines d’entre elles expliquent une grande part de l’hétérogénéité clinique. Des expériences de mutagenèse dirigée ont permis de mieux comprendre la pathophysiologie cellulaire de l’HPP, de classer les allèles selon leur sévérité et leur effet dominant négatif, et de proposer des explications moléculaires au mode de transmission dominant. Un des apports significatifs de la génétique aura été de montrer qu’il y a deux HPP, l’HPP sévère, récessive et rare, et l’HPP modérée, récessive ou dominante, beaucoup moins rare et probablement sous-diagnostiquée. La prévalence des formes sévères a été estimée à 1/300 000 en France et en Europe du Nord, celle des formes modérées pourrait atteindre 1/6 370.

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Introduction

Hypophosphatasia (HPP) is a hereditary disease that mainly affects bone and dental mineralization [1, 2, 3].

HPP is also a multiple system disease with, in particular, neurological, muscular and renal manifestations. HPP is due to loss of function of the ALPL gene encoding TNSALP. This enzyme is a phosphomonoesterase located on the extracellular surface of the plasma membrane and is functional in homodimeric and, perhaps, homotetrameric form [4]. The enzyme dephosphorylates a variety of substrates, including inorganic pyrophosphate (PPi), a central player in bone mineralization, pyridoxal phosphate (PLP), a cofactor in the synthesis of the neurotransmitter gamma-aminobutyric acid (GABA), adenosine monophosphate (AMP), involved in the antinociceptive response, other nucleotides and phosphoethanolamine [5, 6, 7]. It is probable that other substrates have yet to be identified. ALPL mutationsresult in deficiency or absence of TNSALP, and in the bone, neurological, musculoskeletal and renal manifestations of HPP. While the severity of the disease is a continuum, the clinical spectrum is extremely broad, ranging from almost total absence of bone mineralization detectable in utero (perinatal form) to very late onset forms emerging in adulthood.

HPP is a single genetic disease that may be inherited in autosomal dominant or autosomal recessive mode with deviations from the mendelian inheritance inducing variable expressivity, including intra-familial variable expressivity and incomplete penetrance. Molecular biology analysis of HPP patients enabled us to further elucidate the genetic bases of the disease.

Heredity

The severe perinatal and the majority of infantile forms are inherited in autosomal recessive mode. In mild forms (benign prenatal, juvenile, adult and odontohypophosphatasia) both the autosomal dominant and autosomal recessive modes of transmission are identified. Over half of the cases of moderate HPP present with heterozygous mutations of ALPL . In milder forms, the dominant inheritance mode is therefore more frequent (Table 1) [8].

Dominant inheritance

Frequently, the clinical signs observed in HPP patients carrying heterozygous ALPL mutations are not observed in his/her parent carrying the same loss of function mutation, indicating incomplete penetrance. Penetrance is defined by the proportion of patients with clinical disease among the carriers of the genotype at risk. While confirmation of the dominant inheritance mode is easy when the genealogy under study consists of numerous relatives, the incomplete penetrance sometimes makes it difficult if only a propositus and his/her parents are available [9, 10]. Confirmation then relies on molecular biology, which demonstrates a single heterozygous mutation despite complete sequencing of ALPL . The study of a cohort of 38 carrier parent – affected child pairs estimated the mean penetrance to be 32%, reducing the a priori risk of recurrence for a couple with an affected child to 16% versus 50% if penetrance was complete [11]. Molecular biology can even refine that figure by estimating the negative dominant effect of the mutation involved.

Recessive inheritance

In the recessive inheritance mode, penetrance is complete and genetic testing evidences two mutant alleles, each inherited from one parent. In a small number of cases (about 5%), a mutation may not be detected despite sequencing the entire coding sequence of ALPL . It is then difficult to confirm the recessive inheritance mode unless the phenotype is severe.

Genetic counseling

Genetic counseling in the context of HPP is complicated by the existence of the recessive and dominant inheritance modes, the incomplete penetrance of the dominant forms, the variable expressivity and the existence of a benign prenatal form that is sometimes difficult to distinguish from the severe prenatal form.

Severe forms

The risk for a couple that has already had a child with severe HPP of having a second child with the same disease is 25%. In the majority of cases the clinical form will be the same or closely related to that of the index case. However, there may be a degree of familial heterogeneity in the clinical presentation of the disease [12, 13]. These observations suggest that the role of environmental or genetic (gene modifiers) may be important. Noteworthy, the coexistence of radically different clinical forms (e.g. perinatal and adult forms) has never been observed in patients carrying the same genotype.

In that context, the molecular diagnosis enables a prenatal diagnosis to couples who already had a child with severe HPP. Diagnosis is based on a chorionic villi specimen at about 11 weeks of pregnancy. Given the frequency of the disease, the risk that a heterozygous parent’s partner is heterozygous is very low (< 1/250) except in the event of consanguinity. Nonetheless, molecular diagnosis is frequently conducted with a view to reassuring the couple. If one of the segregating mutations in the family has a negative dominant effect, a familial study may be done to test symptomatic relatives. The unborn child may bear one heterozygous ALPL mutation leading to a mild HPP while the index case is affected by a severe form due to an heterozygous compound ALPL mutation.

Moderate forms

In moderate forms, the risk of recurrence depends on the mode of inheritance: 25% if it is recessive, 50% or less, due to the incomplete penetrance, if it is dominant. As stated above, intra-familial clinical heterogeneity is more frequent with dominant transmission than with recessive transmission. Testing for ALPL mutations essentially enables diagnosis and rules out other diseases, in particular Osteogenesis Imperfecta [14]. For heterozygous patients, like patients carrying two mutant alleles, we recommend testing the spouse even though the risk of having a child with severe HPP is very low.

Benign prenatal form

Benign prenatal HPP was first described in 1999 by Pauli et al. and Moore et al. [15, 16]. It is detectable in utero but may have a positive course during the third trimester of pregnancy, unlike the severe prenatal form, which is almost always lethal. The ultrasound and radiological signs are frequently worrying and sometimes difficult to distinguish from those of the severe prenatal form, including short curved long bones and, rarely defective mineralization [17, 18]. The data accumulated on that rare form of HPP have shown that, postanatally, it covers the entire clinical spectrum from relatively severe infantile forms to odontological forms. In consequence, the label ‘non-lethal prenatal form’ has been proposed [17].

The heredity of the benign prenatal form was dominant in two thirds of the cases in our cohort (Table 1) and in 37% of cases according to a 2011 study of 17 new cases and 24 cases derived from the literature [17]. Molecular biology, through the identification of a single heterozygous mutation, rules out a lethal prenatal form since the latter is always inherited in the autosomal recessive mode [14]. Surprisingly, when transmission is dominant the mutation inherited by the fetus is of maternal origin in 85% of cases [17]. This parental transmission bias suggests that the mother contributes to the fetal mineralization process in early fetal development and that her heterozygosity for the mutation no longer enables her to fulfill that function correctly.

Molecular aspects

Currently, more than 315 different mutations of ALPL have been identified worldwide (ALPL gene mutation database: 03_hypo_mutations.php). The genetic heterogeneity affects both the severe and moderate forms of the disease and largely explains the clinical variability observed. Seventy-five percent of the mutations are missense mutations that may confer a variable degree of residual activity to the protein, depending on the amino acid affected and the nature of the substitute amino-acid. Moreover, some of the mutations have a negative dominant effect whose power varies between mutations. This contributes to the clinical heterogeneity [8]. Negative dominant effect mutations are found in recessive forms, associated with other mutations, and are responsible for severe HPP. Because the majority of patients are compound heterozygotes, and because most of the genotypes are ‘private’, i.e. never found in other patients (except relatives), it is almost impossible to predict the genotype/phenotype relationship. There are, however, exceptions due to founder effects resulting in locally recurrent mutations and genotypes [19, 20, 21, 22, 23].

ALPL sequencing enables detection of the mutations and confirmation of the diagnosis of HPP previously suggested by the physical examination, imaging and laboratory test findings. In difficult cases, sequencing confirms the diagnosis and determines the mode of inheritance, an information of importance in the context of genetic counseling. ALPL mutations are almost always inherited. De novo mutations are exceptional irrespective of the transmission mode considered [24, 25]. Lastly, two cases of recessive HPP due to singleparent disomy of chromosome 1 have been reported [26, 27].

Genotype-phenotype relationships

The inverse correlation between a patient’s serum alkaline phosphatase level and phenotype severity has long been known [28]. Since most patients with recessive HPP are compound heterozygotes for two missense mutations, the characterization of the residual activity of the mutated enzyme could be necessary through functional tests using directed mutagenesis tools. Such studies have enabled further elucidation of the cell pathophysiology of HPP, classification of the alleles by their severity and negative dominant effect, and proposal of molecular explanations for the dominant transmission mode.

A large number of mutations have thus been tested by several teams. Residual activity varies widely between mutations, which likely explains the marked clinical heterogeneity among HPP patients (ALPL gene mutation database): 03_hypo_mutations.php). Most of the mutations observed in the severe forms do not induce residual enzymatic activity and affect regions of the protein that are important from a functional or structural point of view such as the active site, crown domain, calcium binding site or homodimeric interface [29, 30, 31, 32, 33]. In contrast, mutations enabling significant residual activity are frequently found in genotypes of HPP patients with moderate forms and frequently in less critical regions of the protein [31].

The effect of those mutations at the cell level has been widely studied, using, in particular, immunohistochemistry, immunofluorescence and confocal microscopy. Often, the mutant protein is unable to dimerize. It may then not be addressed to the cell membrane (its normal destination) and remains trapped in the cytoplasm, where it accumulates before being degraded [34, 35, 36]. In heterozygotes, the protein may form aggregates that trap the wild-type protein, resulting in a negative dominant effect, which explains the dominant transmission mode observed in some cases of moderate HPP. Other mutations seem to prevent dimerization but not membrane addressing [33, 37]. In heterozygotes, the membrane may then become saturated with non-functional monomeric proteins that compete with the functional dimers produced by the wild-type allele, resulting in a negative dominant effect.

Functional tests measure the level of the negative dominant effect of ALPL mutations through the evaluation of the residual enzymatic activity of heterozygous cells. The results again show great variability between mutations, contributing to the marked clinical heterogeneity [8]. Lastly, it is now considered that a large part of the clinical heterogeneity in HPP is due to the variable residual activity of the missense mutations combined with the effect, of variable strength, of the negative dominant effect of some mutations. A genetic model has been proposed, in which the four possible alleles (normal, moderate, severe and dominant severe) combine to produce the ten possible genotypes and three phenotypes (normal, moderate, severe) [11] (Table 2). Nonetheless, it remains difficult to reliably predict the severity of a phenotype on the basis of a genotype, likely because of other genetic or non-genetic factors, but also because the tests only provide an imperfect reflection of a more complex situation in vivo . The murine model may be more reliable to integrate the complexity of genetic and environmental factors [38, 39].

Epidemiological data

Since HPP was described by Rathbun in 1948, it has been classified as a very rare hereditary disease [40]. Genetics contributed significantly to demonstrate that there are in fact two forms of HPP, severe HPP, recessive and rare, and moderate HPP, recessive or dominant, much more frequent and probably under diagnosed.

Severe forms

Fraser estimated the prevalence of severe forms in Canada to be 1/100,000 using pediatric registries. The prevalence in France and in Northern Europe was estimated to be 1/300,000 on the basis of molecular diagnostics [11, 41]. There are marked regional variations. In the Canadian Mennonite community, prevalence reaches 1/2,500 (1 heterozygote out of 25), which is greater than the prevalence of cystic fibrosis in North West Europe. The particularly high prevalence is probably due to the characteristics of the population (small population and consanguinity) [42, 43]. Fraser’s study in Canada was conducted in the Toronto area where the Canadian Mennonite community resides. Overestimation of the prevalence of severe forms cannot be ruled out. In contrast, the disease seems exceptional in the African American population: only one case has been reported [44]. In Japan, the prevalence of the perinatal form is estimated to be about 1/400,000. The combined data from two publications suggest that the prevalence of severe forms (perinatal and infantile) may be about 1/150,000 [1, 23, 45, 46]. The disease has also been reported in China but no estimate is available [47, 48, 49].

Moderate forms

The prevalence of moderate forms of HPP is probably much higher than that of severe forms since heterozygotes may be affected if they carry a dominant mutation. Heterozygotes are much more numerous in the general population (1/270 in France) than homozygotes or compound heterozygotes (1/300,000), the only genotypes inducing disease in the recessive form. Taking into account the proportion of dominant mutations and the mean penetrance, the prevalence of moderate forms may reach 1/6,370 in France and Northern Europe, suggesting that those forms are markedly under diagnosed [11]. Recently, the systematic sequencing of ALPL for adults presenting with abnormally low alkaline phosphatase levels and symptoms suggestive of HPP (low bone mineralization, diffuse joint pain, calcifications, osteoporosis, atypical fractures) revealed numerous heterozygotes ALPL mutations likely deleterious for the protein [14, 50]. This suggests that mild forms are hitherto not diagnosed and belong to this large clinical spectrum that is called HPP.

Conclusion

Our understanding of HPP has progressed considerably over the last 15 years. Genetic advances have greatly contributed to the progress by proposing a genetic model of the disease, estimates of the prevalence of severe and moderate forms, a basis for genotype-phenotype correlation, and a molecular explanation for the dominant transmission mode. Progress have resulted in the emergence of questions that have yet to be elucidated, particularly with respect to the role of genetic and environmental factors in phenotype expression and their respective importance.


Statements of interests

The author reports honoraria for expertise from Alexion.

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