全周 (9AM - 6PM)

我们和你在一起

Extra info thumb
ECTONUCLEOTIDE PYROPHOSPHATASE/PHOSPHODIESTERASE 1; ENPP1

ECTONUCLEOTIDE PYROPHOSPHATASE/PHOSPHODIESTERASE 1; ENPP1

Alternative titles; symbolsPHOSPHODIESTERASE I/NUCLEOTIDE PYROPHOSPHATASE 1; PDNP1PLASMA CELL MEMBRANE GLYCOPROTEIN PC-1; PC1PCA1MEMBRANE COMPONENT, CHROMOSOME 6...

Alternative titles; symbols

  • PHOSPHODIESTERASE I/NUCLEOTIDE PYROPHOSPHATASE 1; PDNP1
  • PLASMA CELL MEMBRANE GLYCOPROTEIN PC-1; PC1
  • PCA1
  • MEMBRANE COMPONENT, CHROMOSOME 6, SURFACE MARKER 1; M6S1
  • LY41, MOUSE, HOMOLOG OF
  • ALKALINE PHOSPHODIESTERASE I
  • NUCLEOTIDE PYROPHOSPHATASE; NPPS

HGNC Approved Gene Symbol: ENPP1

Cytogenetic location: 6q23.2 Genomic coordinates (GRCh38): 6:131,808,019-131,895,154 (from NCBI)

▼ Cloning and Expression
Buckley et al. (1990) described the isolation of cDNA clones encoding the human homolog of the murine Pca-1 protein. The amino acid sequence of the human protein was about 80% identical to the murine protein, although the extent of homology varied in different domains. Southern blots suggested the presence of a single-copy gene. In situ chromosomal hybridization localized the gene to 6q22-q23, a common site for deletions in human lymphoid neoplasia. Also known as membrane component, chromosome 6, surface marker-1 (M6S1), PC1 is the human homolog of Ly-41 in the mouse. Buckley and Goding (1992) demonstrated that the mouse locus, Pca-1, is linked to Myb (189990) on mouse chromosome 10 (Sakaguchi et al., 1984).

▼ Gene Function
In the mouse, the cell membrane glycoprotein Pca-1 is a homodimer with restricted tissue distribution, being first characterized in plasma cells (Takahashi et al., 1970). The sequence of PC1 cDNA indicates that it is a class II transmembrane glycoprotein with a short NH2 cytoplasmic tail, a single transmembrane domain, and a large extracellular C-terminal domain (van Driel and Goding, 1987). Rebbe et al. (1991) showed that PC1 is identical to the enzymes alkaline phosphodiesterase I (EC 3.1.4.1) and nucleotide pyrophosphatase (EC 3.6.1.9). In addition to its expression on plasma cells, PC1 is expressed on hepatocytes, renal tubules, salivary duct epithelium, epididymis, capillary endothelium in the brain, and chondrocytes (Harahap and Goding, 1988).

A bone and cartilage enzyme with both 5-prime-nucleotide phosphodiesterase I and nucleotide pyrophosphohydrolase activity modulates physiologic mineralization and pathologic chondrocalcinosis by generating inorganic pyrophosphate. Huang et al. (1994) hypothesized that, as for liver-bone-kidney alkaline phosphatase, expression of a gene for an enzyme with these properties might be shared by cells from bone, cartilage, liver, and certain leukocytes. They demonstrated that indeed both murine and human plasma cell membrane glycoprotein PC1 is shared by liver, bone, and cartilage cells and has both 5-prime-nucleotide phosphodiesterase I and nucleotide pyrophosphohydrolase activity. In osteosarcoma cells, PC1 expression was increased by transforming growth factor-beta (190180).

Most patients with noninsulin-dependent diabetes mellitus (NIDDM; 125853) are resistant to both endogenous and exogenous insulin. Insulin resistance precedes the onset of this disease, suggesting that it may be an initial abnormality. Insulin receptor kinase activity is impaired in muscle, fibroblasts, and other tissues of many patients with NIDDM, but abnormalities of the insulin receptor gene (INSR; 147670) do not appear to be the cause of this decreased kinase activity. Skin fibroblasts from some insulin-resistant patients contain an inhibitor of insulin-receptor tyrosine kinase. Maddux et al. (1995) showed that this inhibitor is the membrane glycoprotein PC1. They found that PC1 activity is increased in fibroblasts from 7 of 9 patients with typical NIDDM. In addition, overexpression of PC1 in transfected cultured cells reduced insulin-stimulated tyrosine kinase activity. Thus, PC1 may have a role in the insulin resistance of NIDDM. The mechanism by which PC1 inhibits insulin receptor activity is unknown. Kahn (1995) reviewed the causes of insulin resistance.

Maddux and Goldfine (2000) showed that membrane glycoprotein PC1 inhibits insulin receptor function by direct interaction with the receptor alpha-subunit.

▼ Molecular Genetics
Susceptibility to Insulin Resistance, Diabetes Mellitus, or Obesity

Pizzuti et al. (1999) described a K121Q variant in the PC1 gene (rs1044498; 173335.0006) and demonstrated that it was strongly associated with insulin resistance (see 125853) in 121 healthy nonobese, nondiabetic Caucasians in Sicily. Compared with 80 KK allele subjects, Q allele carriers showed higher glucose and insulin levels during oral glucose tolerance tests and insulin resistance by euglycemic clamp. Q carriers had a higher risk of being hyperinsulinemic and insulin resistant. Insulin receptor autophosphorylation was reduced in cultured skin fibroblasts from KQ versus KK subjects. The results suggested that a Q-containing genotype may identify individuals who are at risk of developing insulin resistance, a condition that predisposes to type 2 diabetes (125853) and coronary artery disease (see 608320).

Generalized Arterial Calcification of Infancy 1

Rutsch et al. (2003) used a candidate gene approach to investigate the basis of ectopic calcification in idiopathic infantile arterial calcification (IIAC), also known as generalized arterial calcification of infancy (GACI1; 208000). They screened for mutations in the ENPP1 gene in 11 unrelated families with GACI and identified mutations in 8 of them, either in homozygous or compound heterozygous state. The mutations were distributed across the coding region from exon 3 to exon 25. In 3 families, both parents were heterozygous with respect to 1 of the mutations identified in the affected individuals. In a fourth, consanguineous family, the affected individual and his father, whose disease phenotype seemed to be compensated by hypophosphatemic rickets, were homozygous with respect for the mutation resulting in the amino acid change arg774 to gln (R774C; 208000.0003). (The R774C variant has been reclassified as a polymorphism.) The authors identified 2 nonsense and 2 frameshift mutations resulting in premature termination codons predicted to disturb ENPP1 function and possibly downregulate mutant mRNA by nonsense-mediated decay (NMD).

In a Taiwanese brother and sister with generalized arterial calcification of infancy who had markedly different clinical courses, Cheng et al. (2005) identified compound heterozygosity for 2 missense mutations in the ENPP1 gene (173335.0008 and 173335.0009).

In 8 patients from 5 families with GACI, Ruf et al. (2005) identified a P305T missense mutation (173335.0016) in the ENPP1 gene. Haplotype analysis suggested a founder effect of British extraction for P305T.

Rutsch et al. (2008) performed genetic analysis of 55 GACI patients and identified homozygosity or compound heterozygosity for 40 different mutations in the ENPP1 gene in 41 (75%) of the 55 patients. The most frequently detected mutation was P305T; Rutsch et al. (2008) noted that P305T was universally lethal when present on both alleles, but stated that no other clear genotype/phenotype correlation was seen.

In 2 Caucasian brothers with GACI, 1 deceased of myocardial infarction 12 hours after birth and 1 healthy at 5 years of age, Dlamini et al. (2009) identified compound heterozygosity for a nonsense mutation and a 2-bp deletion in the ENPP1 gene (173335.0014 and 173335.0015, respectively).

In 2 patients with GACI who developed features of pseudoxanthoma elasticum (PXE; 264800) in later childhood, Nitschke et al. (2012) identified homozygous and compound heterozygous mutations in the ENNP1 gene (173335.0017-173335.0019, respectively). Nitschke et al. (2012) also provided follow-up on the living brother previously studied by Dlamini et al. (2009) (see 173335.0014), who at the age of 8 years developed skin lesions characteristic of PXE, the diagnosis of which was confirmed histologically.

In 3 sibs and an unrelated infant, born to 2 consanguineous Bedouin families, with GACI1, Staretz-Chacham et al. (2019) identified homozygosity for a missense mutation in the ENPPI gene (G186R; 173335.0023). All of the patients had thrombocytopenia and cardiac, hepatic, and CNS involvement, and all died in infancy. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing.

Autosomal Recessive Hypophosphatemic Rickets 2

In a cohort of 60 probands with autosomal recessive hypophosphatemic rickets (ARHR2; 613312) who were negative for mutation in known hypophosphatemia genes, Lorenz-Depiereux et al. (2010) sequenced the candidate gene ENPP1 and identified homozygosity for a deletion, and missense and frameshift mutations in 4 families (173335.0010-173335.0012) that were not found in 355 controls. In 1 family, previously studied by Rutsch et al. (2003) (family 4), a father and son who were both homozygous for a missense mutation (G266V; 173335.0011) had different phenotypes: the father had hypophosphatemic rickets, whereas his son had severe GACI. Lorenz-Depiereux et al. (2010) found inappropriately elevated plasma FGF23 (605380) levels in all 6 patients with ENPP1 mutations and concluded that this is the fourth gene (in addition to PHEX (300550), DMP1 (600980), and FGF23 itself) that, if mutated, causes hypophosphatemic rickets due to elevated FGF23 levels.

In a Bedouin family with ARHR mapping to chromosome 6q23, Levy-Litan et al. (2010) sequenced the candidate gene ENPP1 and identified homozygosity for a missense mutation (Y901S; 173335.0013) that segregated with disease and was not found in 236 Bedouin controls from the same geographic region. Functional studies in transfected COS-7 cells showed that the Y901S mutant had significantly lower activity than wildtype.

Cole Disease

In affected members of 3 families with hypopigmented macules primarily over the extremities and hyperkeratotic papules of the palms and soles (COLED; 615522), Eytan et al. (2013) identified heterozygosity for 3 different missense mutations in the ENPP1 gene (173335.0020-173335.0022). Review of clinical data revealed calcinosis cutis or early-onset calcific tendinopathy in some patients from each family. Serum phosphate and fasting glucose levels were normal in the patients tested.

Associations Pending Confirmation

Conflicting reports by Nakamura et al. (1999), Koshizuka et al. (2002) and Horikoshi et al. (2006) have called into question the association of mutation in the ENPP1 gene and ossification of posterior longitudinal ligament of the spine (OPLL; 602475).

To investigate a possible role of NPPS in the etiology of ossification of the posterior longitudinal ligament of the spine, Nakamura et al. (1999) examined its genetic variations in OPLL patients. A total of 323 OPLL patients were screened by means of PCR/SSCP analysis covering all the exons and their surrounding introns, plus about 1.5 kb of the promoter region. They identified 10 nucleotide variations in the NPPS gene; 5 of the alterations caused amino acid substitutions, and 2 of them were found specifically in OPLL patients. Subsequently, Nakamura et al. (1999) performed an association study using these variations and found a significant association of OPLL with 1 allele: a deletion of T at a position 11 nucleotides upstream from the splice acceptor site of intron 20 (IVS20-11delT; 173335.0001). The proportion of individuals having this deletion was significantly higher (p = 0.0029) in OPLL patients than in controls, indicating that those who have this variation may be more susceptible to the abnormal ossification of the spinal ligaments. In a case-control study of 711 Japanese individuals with OPLL and 896 Japanese controls, Horikoshi et al. (2006) found no association between OPLL and a SNP in the ENPP1 gene previously reported by Koshizuka et al. (2002).

▼ Animal Model
Okawa et al. (1998) identified mutations in the Npps gene in a mouse model of ossification of the posterior longitudinal ligament of the spine (OPLL; 602475). Rutsch et al. (2003) pointed out that spontaneous periarticular and aortic calcifications in early life and systemic lowering of nucleotide pyrophosphatase/phosphodiesterase activity and inorganic pyrophosphate levels had been suggested to be shared features of the phenotype of idiopathic infantile arterial calcification (208000) and homozygous 'tiptoe walker' (ttw/ttw) mice, which carry a spontaneous nonsense mutation in Enpp1.

Using high-resolution micro-CT, Thumbigere-Math et al. (2018) analyzed the mandibular molars of Enpp1-null mice and observed a 4-fold increased cervical cementum thickness and 5-fold increase in volume compared to wildtype mice, as well as a nonsignificant 5% increase in mineral density. Apically located cellular cementum showed significantly increased volume and height on the mesial root surface, but no change in thickness or density in the null mice compared to wildtype. The authors noted that histologically the molars of Enpp1-null mice resembled those of GACI patients, including dramatically expanded cervical cementum with abnormal inclusion of embedded nucleated cementocyte-like cells and lacunae.

▼ ALLELIC VARIANTS ( 23 Selected Examples):

.0001 TYPE 2 DIABETES MELLITUS, SUSCEPTIBILITY TO
OBESITY, SUSCEPTIBILITY TO, INCLUDED
ENPP1, IVS20AS, 1-BP DEL, T, -11
Type 2 Diabetes Mellitus and Obesity

Meyre et al. (2005) identified this polymorphism, deletion of a T at position -11 in the IVS20 acceptor splice site, as 1 of 3 that defined a risk haplotype for childhood or adult obesity (601665) and type II diabetes (125853). See 173335.0006.

Possible Association with Ossification of Posterior Longitudinal Ligament of the Spine

Conflicting reports have called the association of this polymorphism with susceptibility to OPLL (602475) into question.

Following the demonstration by Okawa et al. (1998) that ttw (tiptoe walking), a seeming mouse model for ossification of the posterior longitudinal ligament of the spine (OPLL; 602475), was caused by a nonsense mutation of the gene encoding nucleotide pyrophosphatase (NPPS), Nakamura et al. (1999) screened 323 OPLL patients for variations in the NPPS gene. A significant association was found between this phenotype and a deletion of T at a position 11 nucleotides upstream from the splice acceptor site of intron 20; the proportion of individuals who had this deletion was significantly higher (p = 0.0029) in OPLL patients than in controls.

In a case-control study of 711 Japanese individuals with OPLL and 896 Japanese controls, Horikoshi et al. (2006) found no association between OPLL and a SNP in the ENPP1 gene previously reported by Koshizuka et al. (2002).

.0002 ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 1
ENPP1, GLU893TER
Rutsch et al. (2001) described an individual with idiopathic infantile arterial calcification (208000) born to consanguineous parents who had reduced levels of expression of ENPP1 but seemed to be heterozygous at the ENPP1 locus on 6q. The mutation was a 2677G-T transversion resulting in a glu893-to-ter (E893X) amino acid change. Using a high-density microsatellite marker panel for 6q, Rutsch et al. (2003) identified a recombination event in the proband that had obscured homozygosity with respect to the critical region. The patient was the only affected sib of 3 children of Turkish extraction, was alive at age 6 years, and showed periarticular calcification.

.0003 RECLASSIFIED - ENPP POLYMORPHISM
ENPP1, ARG774CYS (rs2893397)
This variant, formerly titled ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY based on Rutsch et al. (2003), has been reclassified based on the footnote in Table 3 of Lorenz-Depiereux et al. (2010) indicating that the R774C variant has been shown to be a polymorphism (rs2893397) with a minor allele frequency of 5%.

In a boy with idiopathic infantile arterial calcification (208000), the only child of consanguineous Turkish parents, Rutsch et al. (2003) described homozygosity for an arg774-to-cys (R774C) mutation, the result of a 2,320C-T transition. The child showed periarticular calcification and was still alive at 3 years of age. Lorenz-Depiereux et al. (2010) restudied this family, in which the child's father had hypophosphatemic rickets, and identified homozygosity for a G266V substitution in the ENPP1 gene (173335.0011) in both father and son.

.0004 ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 1
ENPP1, 11-BP DEL, NT1072
In a German infant with idiopathic infantile arterial calcification (GACI1; 208000), Rutsch et al. (2003) demonstrated an 11-bp deletion in the ENPP1 gene (nucleotides 1072-1082) resulting in the frameshift mutation Gln358fsTer359. The deletion was present in compound heterozygous state with a second allele containing 2 missense changes, leu579 to phe (L579F; 173335.0005) and arg774 to cys (R774C; 173335.0003). The proband was the only affected in a sibship of 3 with nonconsanguineous parents. The infant died at age 29 days and showed no periarticular calcification.

.0005 ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 1
ENPP1, LEU579PHE
For discussion of the leu579-to-phe (L579F) mutation in the ENPP1 gene that was found in compound heterozygous state in a Turkish boy with generalized arterial calcification of infancy (GACI1; 208000) by Rutsch et al. (2003), see 173335.0004.

.0006 INSULIN RESISTANCE, SUSCEPTIBILITY TO
TYPE 2 DIABETES MELLITUS, SUSCEPTIBILITY TO, INCLUDED
OBESITY, SUSCEPTIBILITY TO, INCLUDED
ENPP1, LYS121GLN
Pizzuti et al. (1999) described a polymorphism in exon 4 of the PC1 gene (K121Q; rs1044498) and demonstrated that it was strongly associated with insulin resistance (see 125853) in 121 healthy nonobese, nondiabetic Caucasians in Sicily. Compared with 80 KK allele subjects, Q allele carriers showed higher glucose and insulin levels during oral glucose tolerance tests and insulin resistance by euglycemic clamp. Q carriers had a higher risk of being hyperinsulinemic and insulin resistant. Insulin receptor autophosphorylation was reduced in cultured skin fibroblasts from KQ versus KK subjects. The results suggested that a Q-containing genotype may identify individuals who are at risk of developing insulin resistance, a condition that predisposes to type II diabetes (125853) and coronary artery disease (see 608320).

Frittitta et al. (2001) investigated whether the PC1 gene modulates insulin sensitivity independently of weight status. Although subjects were nondiabetic by selection criteria, plasma insulin concentrations during oral glucose tolerance test were higher (P less than 0.05) in Q allele-carrying subjects (K121Q or Q121Q genotypes), compared with K121K individuals, in both the nonobese and obese groups. The K121Q polymorphism was correlated with insulin sensitivity independently (P less than 0.05) of BMI, gender, age, and waist circumference. The authors concluded that the Q121 PC1 variant and obesity (601665) have independent and additive effects in causing insulin resistance.

Abate et al. (2003) determined the frequency of the PC1 K121Q and IRS1 G972R (147545.0002) polymorphisms in Asian Indians and Caucasians. (The authors referred to the IRS1 polymorphism as G972A.) The Asian Indian group included both subjects who had immigrated to the United States and those who were born in the United States. The frequency of carrying at least 1 copy of the PC1 121Q variant in Asian Indians was significantly higher than that in Caucasians (P = 0.01), but the frequency was similar for IRS1 972R (6% and 7%). A significantly higher insulin area under the curve during oral glucose tolerance testing (P less than 0.0001) and lower insulin sensitivity during glucose clamp studies (P = 0.04) were found in Asian Indians with the PC1 121Q variant compared with Asian Indians with wildtype PC1 and with Caucasians with or without the polymorphism. IRS1 972R was not associated with any change in insulin sensitivity. The authors concluded that the PC1 K121Q polymorphism associates with primary insulin resistance in migrant Asian Indians.

Hamaguchi et al. (2004) studied the prevalence of PC1 Q121 in a Dominican Republic population (755 subjects studied) and whether this variant is associated with insulin resistance, obesity, or type II diabetes. The prevalence of PC1 Q121 was high compared with that in other populations. The proportions of genotypes detected were: KK, 21.6%; KQ, 48.3%; and QQ, 30.1%. This compares to approximately 74%, 24%, and 2% in other populations. Among nonobese nondiabetic subjects, the insulin response of KQ (P = 0.027) and QQ (P = 0.031) subjects was greater during the oral glucose tolerance test than that of KK subjects, whereas plasma glucose profiles were comparable. The Q allele was more prevalent in obese type II diabetics than in controls (P = 0.026; odds ratio = 1.56). Multiple regression analysis, after adjusting for age, gender, and body mass index (BMI), showed the QQ genotype to be associated with type II diabetes (P = 0.043; odds ratio = 2.74) but not obesity (P = 0.068). The authors concluded that the PC1 Q121 allele is exceptionally prevalent in the Dominican Republic, contributing to both insulin resistance and type II diabetes.

Kubaszek et al. (2004) investigated whether the effect of the K121Q polymorphism on insulin sensitivity, and the occurrence of diabetes and hypertension, depends on size at birth. In a study of 489 subjects born in Helsinki between 1924 and 1933, they found that fasting insulin levels and insulin resistance were highest in subjects carrying the 121Q allele who were small at birth (P for interaction = 0.04 and 0.05). Additionally, in those whose birth length was up to 49 cm, the K121Q polymorphism was associated with a 2-fold higher incidence of type II diabetes. Kubaszek et al. (2004) concluded that the effect of the K121Q polymorphism on insulin levels and insulin sensitivity, measured as the homeostasis model assessment for insulin resistance, is dependent on birth length and that this interaction increases susceptibility to type II diabetes and hypertension in adulthood.

Meyre et al. (2005) analyzed the ENPP1 gene in 6,147 subjects and found an association between a 3-allele risk haplotype defined by the polymorphisms K121Q, IVS20delT-11 (173335.0001), and A-G+1044TGA (173335.0007) and childhood obesity (odds ratio = 1.69, P = 0.0006), morbid or moderate obesity in adults (odds ratio = 1.50, P = 0.006 or odds ratio = 1.37, P = 0.02, respectively), and type II diabetes (odds ratio = 1.56, P = 0.00002). The Genotype IBD Sharing Test suggested that this obesity-associated ENPP1 risk haplotype, which they referred to as QdelTG, contributes to the chromosome 6q linkage in childhood obesity reported by Meyre et al. (2004). The haplotype confers a higher risk of glucose intolerance with type II diabetes to obese children and their parents and associates with increased serum levels of soluble ENPP1 protein in children. Expression of a long ENPP1 mRNA isoform, which includes the obesity-associated A-G+1044TGA SNP, was specific for pancreatic islet beta cells, adipocytes, and liver. Meyre et al. (2004) concluded that several variants of ENPP1 have a primary role in mediating insulin resistance and in the development of both obesity and type II diabetes, suggesting that an underlying molecular mechanism is common to both conditions.

Bottcher et al. (2006) genotyped the K121Q, IVS20delT-11, and A/G+1044TGA ENPP1 genetic variants for association analyses in 712 school children and in independent cohorts of 205 obese children from Leipzig and 195 obese children from Datteln, Germany. They identified a significantly increased risk of obesity in Leipzig children carrying the 121Q variant (adjusted odds ratio, 1.82; 95% confidence interval, 1.30-2.56; P = 0.0005) or the Q-delT-G haplotype (1.75 (1.17-2.62), P = 0.006) as compared with a lean control group. Bottcher et al. (2006) concluded that their study suggested a potential role of the K121Q polymorphism or derived ENPP1 haplotypes in increased susceptibility to obesity and early impairment of glucose and insulin metabolism in children.

In a case-control study of 911 unrelated Japanese patients with type II diabetes and 876 Japanese controls, Keshavarz et al. (2006) found no significant differences in genotype distribution or allele frequency of the K121Q variant between the 2 groups. Keshavarz et al. (2006) concluded that K121Q has little if any impact on type II diabetes susceptibility in the Japanese population.

.0007 OBESITY, SUSCEPTIBILITY TO
ENPP1, A-G1044TGA
Meyre et al. (2004) stated that the A-G1044TGA 3-prime SNP of the ENPP1 gene is associated with obesity (601665). The A-G1044TGA SNP is included in an isoform specifically expressed in 3 highly insulin-responsive human tissues (pancreatic islet beta cell, adipocyte, and liver). Mice given an adenovirus expression construct expressing this isoform in hepatocytes showed insulin resistance and glucose intolerance (Dong et al., 2005).

.0008 ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 1
ENPP1, GLY342VAL
In 2 Taiwanese sibs with generalized arterial calcification of infancy (GACI1; 208000), Cheng et al. (2005) identified compound heterozygosity for a 1025G-T and a 1112A-T transversion in the ENPP1 gene, resulting in a gly342-to-val (G342V) and a tyr371-to-phe (Y371F; 173335.0009) substitution, respectively. Despite their identical genotype, the sibs had markedly different clinical courses: the male infant died with severe heart failure and hypertension at the age of 6 weeks, whereas the female infant had no complications upon examination at 18 months of age.

.0009 ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 1
ENPP1, TYR371PHE
For discussion of the 1112A-T transversion in the ENPP1 gene, resulting in a tyr371-to-phe (Y371F) substitution, that was found in compound heterozygous state in 2 Taiwanese sibs with generalized arterial calcification of infancy (GACI1; 208000) by Cheng et al. (2005), see 173335.0008.

.0010 HYPOPHOSPHATEMIC RICKETS, AUTOSOMAL RECESSIVE, 2
ENPP1, EX24-25DEL
In 2 Turkish brothers with autosomal recessive hypophosphatemic rickets-2 (ARHR2; 613312), Lorenz-Depiereux et al. (2010) identified homozygosity for a deletion of the last 2 exons (24 and 25) of the ENPP1 gene, predicted to truncate the C-terminal part of the nuclease-like domain. The breakpoints lie within single-copy sequences in intron 23 and the 3-prime UTR.

.0011 HYPOPHOSPHATEMIC RICKETS, AUTOSOMAL RECESSIVE, 2
ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 1, INCLUDED
ENPP1, GLY266VAL
In 2 unrelated Turkish families with autosomal recessive hypophosphatemic rickets-2 (ARHR2; 613312), Lorenz-Depiereux et al. (2010) identified homozygosity for a 797G-T transversion in exon 8 of the ENPP1 gene, resulting in a gly266-to-val (G266V) substitution at a highly conserved residue within the catalytic domain. The mutation was not found in 184 European, 83 Turkish, or 92 Israeli-Arab controls. In 1 of the families, which had previously been studied by Rutsch et al. (2003) (family 4), a father and son who were both homozygous for G266V had different phenotypes: the father had hypophosphatemic rickets, whereas the son had severe generalized arterial calcification of infancy (GACI1; 208000) and hypophosphatemia. The father, who developed aortic root dissection at 28 years of age, underwent ultrasound of the large vessels that showed normal carotid and renal arteries and a normal thoracic and abdominal aorta. Rutsch et al. (2003) had previously identified homozygosity for an R774C mutation in the ENPP1 gene (173335.0003) in the father and son.

.0012 HYPOPHOSPHATEMIC RICKETS, AUTOSOMAL RECESSIVE, 2
ENPP1, 1-BP INS, 2248A
In an Israeli Arab male patient with autosomal recessive hypophosphatemic rickets-2 (ARHR2; 613312), Lorenz-Depiereux et al. (2010) identified homozygosity for a 1-bp insertion (2248insA) in exon 22 of the ENPP1 gene, resulting in a frameshift and premature termination after 5 codons, disrupting most of the nuclease-like domain. The mutation was not found in 184 European, 83 Turkish, or 92 Israeli-Arab controls.

.0013 HYPOPHOSPHATEMIC RICKETS, AUTOSOMAL RECESSIVE, 2
ENPP1, TYR901SER
In 2 brothers and their male cousin from a consanguineous Bedouin family with autosomal recessive hypophosphatemic rickets-2 (ARHR2; 613312), Levy-Litan et al. (2010) identified homozygosity for a 2722A-C transversion in the ENPP1 gene, resulting in a tyr901-to-ser (Y901S) substitution at a strictly conserved residue. The parents were heterozygous for the mutation, which was not found in 236 Bedouin controls from the same geographic region. Functional studies in transfected COS-7 cells demonstrated that the Y901S mutant had significantly lower activity than wildtype, although immunofluorescence showed similar localization to the cell membrane.

.0014 ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 1
ENPP1, TYR261TER
In 2 Caucasian brothers with generalized arterial calcification of infancy (GACI1; 208000), 1 deceased of myocardial infarction 12 hours after birth and 1 healthy at 5 years of age, Dlamini et al. (2009) identified compound heterozygosity for a 783C-G transversion in exon 7 of the ENPP1 gene, resulting in a tyr261-to-ter (Y261X) substitution, and a 2-bp deletion (878delAA; 173335.0015) in exon 8, causing a frameshift and premature termination. The unaffected parents were each heterozygous for 1 of the mutations. A third female sib was stillborn and had shown echogenicity of the myocardium and aortic root suggestive of calcification on prenatal ultrasound. Genetic analysis was declined in the stillborn sib.

Nitschke et al. (2012) provided follow-up on the living brother previously studied by Dlamini et al. (2009), who at the age of 8 years developed pseudoxanthomatous skin lesions around his umbilicus and on his neck, which were histologically proven to be typical lesions of pseudoxanthoma elasticum (PXE; 264800).

.0015 ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 1
ENPP1, 2-BP DEL, 878AA
For discussion of the 2-bp deletion (878delAA) in exon 8 of the ENPP1 gene, causing a frameshift and premature termination, that was found in compound heterozygous state in 2 Caucasian brothers with generalized arterial calcification of infancy (GACI1; 208000) by Dlamini et al. (2009), see 173335.0014.

.0016 ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 1
ENPP1, PRO305THR
In 8 patients from 5 families with generalized arterial calcification of infancy-1 (GACI1; 208000), including 2 previously reported patients (patient 1, Van de Woestijne et al., 1988; patient 3a, Ciana et al., 1997), Ruf et al. (2005) identified homozygosity or compound heterozygosity for a 913C-A transversion in the ENPP1 gene, resulting in a pro305-to-thr (P305T) substitution. Haplotype analysis suggested a founder effect of British extraction for P305T.

Rutsch et al. (2008) identified homozygosity or compound heterozygosity for the P305T mutation in the ENPP1 gene in 12 patients with GACI, 3 of whom had previously been studied by Ruf et al. (2005). All 5 patients who were homozygous for P305T died in infancy.

.0017 ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 1
ENPP1, ASP538HIS
In a 12-year-old boy with generalized arterial calcification of infancy-1 (GACI1; 208000), born of consanguineous French parents, Nitschke et al. (2012) identified homozygosity for a 1612G-C transversion in exon 16 of the ENPP1 gene, resulting in an asp538-to-his (D538H) substitution at a conserved residue in the catalytic domain. Oral bisphosphonate treatment resulted in the disappearance of ectopic calcifications by 4 years of age. At 9 years of age, the patient developed yellowish papules on the neck and periumbilical region and large angiomatous atrophic macules; histology was consistent with that of lesions in pseudoxanthoma elasticum (PXE; 264800). He also had hypophosphatemic rickets, abnormal calcifications of the ear cartilage, cervical fusion between C3 and C5, and microcalcifications of the left kidney. At 12 years of age, he developed otosclerosis with stapedovestibular ankylosis, resulting in hearing loss. The patient's mother also presented yellow papules characteristic of PXE, and his 9-year-old sister had angiomatous linear lesions of the left flank.

.0018 ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 1
ENPP1, IVS7DS, G-A, +1
In a 5-year-old girl with generalized arterial calcification of infancy-1 (208000), born of nonconsanguineous French parents, Nitschke et al. (2012) identified compound heterozygosity for a 795+1G-A transition in intron 7 of the ENPP1 gene on the maternal chromosome, predicted to cause loss of the donor splice site and aberrant splicing, and a 1756G-A transition in exon 18 of the ENPP1 gene on the paternal chromosome, resulting in a gly586-to-arg (G586R; 173335.0019) substitution at a conserved residue in the catalytic domain. The patient had short stature, hypophosphatemic rickets, and cardiovascular, pancreatic, hepatic, and renal calcifications, as well as diffuse angiomatous lesions on her back and angioid streaks in the Bruch membrane of the retina that were typical for pseudoxanthoma elasticum (PXE; 264800). She did not have any pseudoxanthomatous skin lesions. At 4 years of age, she had also developed conductive deafness and required hearing aids.

.0019 ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 1
ENPP1, GLY586ARG
For discussion of the 1756G-A transition in exon 18 of the ENPP1 gene, resulting in a gly586-to-arg (G586R) substitution, found in compound heterozygous state in a girl with generalized arterial calcification of infancy (GACI1; 208000) by Nitschke et al. (2012), see 173335.0018.

.0020 COLE DISEASE
ENPP1, CYS177TYR
In affected members of a 3-generation French family with hypopigmented macules primarily over the extremities and hyperkeratotic papules of the palms and soles (COLED; 615522), Eytan et al. (2013) identified heterozygosity for a c.530G-A transition in exon 4 of the ENPP1 gene, resulting in a cys177-to-tyr (C177Y) substitution at a highly conserved residue in the SMB2 domain. The mutation segregated with disease in the family and was not found in dbSNP, the Human Gene Mutation Database, the UCSC Genome Browser, 1000 Genomes, Ensembl, or the NHLBI Exome Variant Server. In addition to skin manifestations, 2 affected family members exhibited early-onset calcific tendinopathy. Normal serum phosphate and fasting glucose levels were found in the 3 affected individuals tested in this family.

.0021 COLE DISEASE
ENPP1, CYS164SER
In a boy with congenital guttate hypopigmentation on his extremities, hyperkeratotic papules on the soles of his feet, and calcinosis cutis (COLED; 615522), originally reported by Moore et al. (2009), Eytan et al. (2013) identified heterozygosity for a 491G-C transversion in exon 4 of the ENPP1 gene, resulting in a cys164-to-ser (C164S) substitution at a highly conserved residue in the SMB2 domain. The mutation segregated with disease in the family and was not found in dbSNP, the Human Gene Mutation Database, the UCSC Genome Browser, 1000 Genomes, Ensembl, or the NHLBI Exome Variant Server. The patient had normal serum phosphate and fasting glucose levels.

.0022 COLE DISEASE
ENPP1, CYS149SER
In affected members of a 4-generation French family with hypopigmented macules primarily over the extremities and hyperkeratotic papules of the palms and soles (COLED; 615522), Eytan et al. (2013) identified heterozygosity for a c.446G-C transversion in exon 4 of the ENPP1 gene, resulting in a cys149-to-ser (C149S) substitution at a highly conserved residue in the SMB2 domain. The mutation segregated with disease in the family and was not found in dbSNP, the Human Gene Mutation Database, the UCSC Genome Browser, 1000 Genomes, Ensembl, or the NHLBI Exome Variant Server. One affected family member exhibited calcinosis cutis. Normal serum phosphate and fasting glucose levels were found in the 1 affected individual tested in this family.

.0023 ARTERIAL CALCIFICATION, GENERALIZED, OF INFANCY, 1
ENPP1, GLY186ARG
In 3 sibs and an unrelated infant, born to 2 consanguineous Bedouin families, with idiopathic infantile arterial calcification (GACI1; 208000), Staretz-Chacham et al. (2019) identified homozygosity for a c.556G-C transversion at the last nucleotide in exon 4 of the ENPP1 gene, resulting in a gly186-to-arg (G186R) substitution in the highly conserved somatomedin B2 domain. The mutation was predicted to result in a deletion of the donor splice site at the end of exon 4, leading to a longer exon 4 with 48 additional amino acids before a premature stop codon. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents of both families. The variant was not reported in the gnomAD database or in an in-house cohort of 2,056 Israeli exomes. In fibroblasts from a carrier parent, mRNA from only the wildtype allele was identified, indicating that the mutant allele is probably degraded through nonsense-mediated decay.

Tags: 6q23.2