Properdin Deficiency, X-Linked

A number sign (#) is used with this entry because properdin deficiency, also known as complement factor properdin deficiency (CFPD), is caused by mutation in the PFC gene (CFP; 300383).

Description

Properdin (factor P) is a plasma protein that is active in the alternative complement pathway of the innate immune system. It is a positive regulatory factor that binds to many microbial surfaces to stabilize the C3b,Bb convertase. Deficiency of properdin is associated in particular with a heightened susceptibility to Neisseria species (Janeway et al., 2001).

Clinical Features

Davis and Forristal (1980) studied 2 families with partial properdin deficiency. In 1 family a brother and sister, and a daughter of the brother, showed deficiency. Two brothers were affected in the second family, with normal properdin levels in 4 sibs and both parents. Partial properdin deficiency was found to be innocuous. The fact that partial deficiency resulted in diminished C3 consumption in the presence of activators of both the alternative and the classic complement pathways suggested that complete absence would severely limit complement activation.

Sjoholm et al. (1982) described a kindred in which 3 males, each in a different sibship (2 maternal first cousins and a maternal uncle of both), were shown to have a selective deficiency of properdin. One of the 3 died from a fulminant infection with Neisseria meningitidis group C. The family history showed 3 previous cases of similar infections with fatal outcome in males related to the 3 patients studied, in a manner consistent with X-linked recessive inheritance (see Ross and Densen, 1984). Heterozygotes were not clearly distinguished.

Densen et al. (1987) reported a large family in which properdin deficiency was associated with meningococcal infection. The proband was a previously healthy 30-year-old man who worked as a logger and died with fulminant group Y meningococcal meningitis. A brother had died of fulminant group B meningococcal disease 16 years earlier at age 18. A second cousin had had 'spinal meningitis' at age 4 and 'black measles' at age 6, and had died of group Y meningococcal disease at age 19 during basic military training. Group Y disease was not epidemic in the recruit camp at that time.

Gelfand et al. (1987) described a third family. The proband was a 9-year-old boy with recurrent pneumococcal bacteremia. His serum had no hemolytic activity in either the classic or alternative complement pathways. Absence of classic pathway activity was found to be secondary to homozygous deficiency of C2. Both parents had half-normal levels of C2, compatible with autosomal recessive inheritance. The proband had profound deficiency of serum properdin. Properdin levels were normal in the father and half-normal in the mother, suggesting X-linked inheritance. Addition of purified properdin to the patient's serum fully reconstituted the alternative pathway function.

Fijen et al. (1989) presented the pedigree of a very large kindred, showing at least 9 affected males in 3 generations and 6 separate sibships. Properdin deficiency was found in 9 of 46 patients in whom meningococcal disease developed after the age of 10 years. All were males. C3 deficiency syndromes (see 613799) were found in 5, and homozygous deficiency of a terminal component (C5, C6, C7, or C8) was found in 9. Meningococcal infections recurred in 5 of the 9 patients with terminal complement component deficiencies but not in the other patients with complement deficiency. The meningococcal disease investigated was due to rare serotypes X, Y, Z, W135, or 29E. The common sera groups, A, B, and C, are seldom associated with complement deficiencies.

Inheritance

Multiple studies have shown that properdin deficiency is inherited as an X-linked recessive trait (Sjoholm et al., 1982, Ross and Densen, 1984, Gelfand et al., 1987).

Tersmette-Steeynstra et al. (1986) described a family with frequent occurrence of meningococcal infections in males in an X-linked recessive pedigree pattern. The findings were consistent with properdin deficiency.

Mensink and Schuurman (1987) stated that 8 families with X-linked recessive inheritance of selective properdin P deficiency were known to them. Some of the patients had fulminant and often fatal meningitis with Neisseria meningitidis. The oldest was 61 years of age. They suggested that this deficiency was not associated with recurrent infections.

In the large family described by Densen et al. (1987), the cousin was related to the 2 brothers mentioned through his maternal grandfather. The pedigree and the laboratory findings were consistent with X-linked recessive inheritance. patient's serum fully reconstituted the alternative pathway function.

Sjoholm et al. (1988) described a family with an X-linked properdin-dysfunctional state, apparently predisposing the affected persons to meningococcal disease. In the affected individuals, circulating levels of properdin were normal by immunochemical assay, but the properdin was functionally defective. Findings in obligate female carriers were consistent with random inactivation of normal and defective properdin alleles, in accordance with the Lyon hypothesis.

Population Genetics

In a study of complement deficiencies among patients with meningococcal disease in Israel, Schlesinger et al. (1990) observed properdin deficiency only in Sephardic Jews of Tunisian origin. A pedigree pattern consistent with X-linked recessive inheritance was described.

By analyzing the hemolytic activity of the classic (CH50) and the alternative (AP50) complement pathways in the sera of 101 survivors of meningococcal infections and 59 survivors of severe pneumococcal and Haemophilus influenza infections, Schlesinger et al. (1993) found 3 propositi with properdin deficiency and identified 6 additional affected family members. They belonged to 3 unrelated families of Tunisian Jews who came to Israel from different parts of Tunisia. Two patients had a meningococcal infection at 15 and 16 years of age, respectively, and one had Haemophilus influenza meningitis at 1.5 years of age. In contrast to the fulminant and fatal course of meningococcal infection that had previously been described in some properdin-deficient patients, these patients had a relatively mild course. They were, of course, selected for survival. However, Schlesinger et al. (1993) suggested that properdin deficiency may not be as rare as generally thought.

Diagnosis

In a brother and maternal uncle of the 2 brothers first mentioned by Densen et al. (1987), properdin deficiency was found by laboratory tests. Unaffected male relatives showed properdin antigen levels averaging 128.0 ELISA units/ml whereas 5 obligate carrier females had levels averaging 45.6 units.

Mapping

In the Swedish family reported by Sjoholm et al. (1982), Goonewardena et al. (1987) tested for linkage with 17 RFLPs of known regional assignment on the X chromosome. Recombination was observed for all except OTC (300461) and DXS7. There were 7 and 5 informative meioses, respectively, for these 2 loci. Goonewardena et al. (1987, 1988) concluded that the locus for properdin deficiency is proximal to the DMD locus. DXS7 is located in band Xp11.3; OTC is located in band Xp21.1; DMD is located in band Xp21.2.

Wadelius et al. (1989) also presented linkage data supporting location of the 'properdin deficiency gene' on the proximal part of Xp.

Using microsatellite and other X-chromosome polymorphisms, Wadelius et al. (1992) performed linkage studies in 6 multigeneration families with different types of properdin deficiency. Based on multipoint data, it was found that the disease gene maps close to DXS255 (maximum lod = 13.3 at theta = 0.00) and DXS426 (maximum lod = 12.9 at theta = 0.00). There was no indication of genetic heterogeneity among the 6 families.

Molecular Genetics

Westberg et al. (1995) used direct solid-phase sequencing of the PFC gene to identify point mutations in type I (300383.0001) and type II (300383.0002) properdin deficiency defined as absent or low serum properdin, respectively. In a Dutch family, Fredrikson et al. (1996) identified a mutation in type III (300383.0005) properdin deficiency, defined as the presence of a dysfunctional properdin protein in serum.

Kolble et al. (1993) used a dinucleotide repeat containing sequence less than 15 kb downstream of the properdin structural gene (Coleman et al., 1991; Nolan et al., 1992) for carrier detection by microsatellite haplotyping. A nonradioisotopic PCR-based method was used for microsatellite detection. Probable and definite carriers frequently showed properdin levels in the normal range. No recombinants between the microsatellite loci and properdin deficiency were detected, thus allowing identification of the defective allele in 3 pedigrees.

In 10 Dutch families, van den Bogaard et al. (2000) identified 2 genetic defects responsible for properdin type I deficiency (300383.0003, 300383.0004). All amino acid substitutions were limited to conserved amino acids in exons 7 and 8, in contrast to premature stops that were found in other exons. Missense mutations may alter the protein conformation in such a way that properdin will not be secreted and therefore catabolized intracellularly. The decreased properdin levels found in some healthy females carrying 1 mutated properdin gene were studied for X inactivation. Most carriers with extremely low or high properdin levels showed preferential X inactivation for the normal or mutated X chromosome, respectively. The authors observed some exceptions, however, suggesting additional regulation of properdin excretion apart from X inactivation. Three unrelated families had the same mutation in exon 7 and another 3 unrelated families had the same mutation in exon 8, suggesting founder effect; the families with an identical properdin defect originated from the same regions within the Netherlands.