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Homozygous Mutations in LPIN2 Are Responsible for the Syndrome Of 551 ORIGINAL ARTICLE Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome) P J Ferguson, S Chen, M K Tayeh, L Ochoa, S M Leal, A Pelet, A Munnich, S Lyonnet, H A Majeed, H El-Shanti ............................................................................................................................... J Med Genet 2005;42:551–557. doi: 10.1136/jmg.2005.030759 Background: Majeed syndrome is an autosomal recessive, autoinflammatory disorder characterised by chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. The objectives of this study were to map, identify, and characterise the Majeed syndrome causal gene and to speculate on its function and role in skin and bone inflammation. Methods: Six individuals with Majeed syndrome from two unrelated families were identified for this study. See end of article for Homozygosity mapping and parametric linkage analysis were employed for the localisation of the gene authors’ affiliations ....................... responsible for Majeed syndrome. Direct sequencing was utilised for the identification of mutations within the genes contained in the region of linkage. Expression studies and in silico characterisation of the Correspondence to: Hatem El-Shanti, University identified causal gene and its protein were carried out. of Iowa Hospital, 2615 Results: The phenotype of Majeed syndrome includes inflammation of the bone and skin, recurrent fevers, JCP, 200 Hawkins Drive, and dyserythropoietic anaemia. The clinical picture of the six affected individuals is briefly reviewed. The Iowa City, IA 52242, USA; gene was mapped to a 5.5 cM interval (1.8 Mb) on chromosome 18p. Examination of genes in this hatem-el-shanti@uiowa. edu interval led to the identification of homozygous mutations in LPIN2 in affected individuals from the two families. LPIN2 was found to be expressed in almost all tissues. The function of LPIN2 and its role in Received 5 January 2005 inflammation remains unknown. Revised version received Conclusions: We conclude that homozygous mutations in LPIN2 result in Majeed syndrome. 16 February 2005 Accepted for publication Understanding the aberrant immune response in this condition will shed light on the aetiology of other 18 February 2005 inflammatory disorders of multifactorial aetiology including isolated chronic recurrent multifocal ....................... osteomyelitis, Sweet syndrome, and psoriasis. ultifactorial disorders, such as psoriasis and inflam- parents, suggesting autosomal recessive inheritance.81516 A matory bowel disease, result from complex interac- published article reports one monozygotic twin pair con- tions between a number of predisposing factors, cordant for CRMO and a second monozygotic twin pair with M 17 including genotypes at one or more loci and a variety of CRMO diagnosed in one twin and PPP in the other. In the environmental exposures that trigger, accelerate, or exacer- same article, the authors report a child with CRMO whose bate the disease process. There are several approaches to the father has developed chronic non-infectious osteomyelitis of identification of aetiologic genetic factors in a complex the sternum as an adult, suggesting autosomal dominant disease, such as genome-wide linkage and association studies inheritance with variable expression. Also, it has been or targeted examination of a specific gene or region. In the recently shown through an association study that there is a latter approach, the specific gene that is targeted in a study is susceptibility locus for isolated CRMO on chromosome chosen due to its physiologic role, its presence in a 18q21.3–22.17 Furthermore, there is a similar murine disorder chromosomal break point, or its causal role in a Mendelian (chronic multifocal osteomyelitis), resulting from a recessive disorder sharing a similar phenotype. The exploration of the mutation in a gene mapped to a region on mouse chromo- role of a rare Mendelian disorder gene in a more common some 18, which is homologous to the human region disorder that shares a phenotype with the Mendelian containing the CRMO susceptibility locus.18 19 disorder has proven successful on multiple occasions, such The high prevalence of consanguinity among Jordanians as in WFS1 and deafness,1 IRF6 and cleft lip and/or palate,2 makes it possible to identify inbred families with rare and rare variations in ABCA1, APOA, and LCAT and low recessive disorders that are large enough to independently plasma levels of HDL cholesterol.3 establish linkage.20–22 In these families, individuals with rare Chronic recurrent multifocal osteomyelitis (CRMO; recessive traits are likely to have inherited both copies of the MIM 259680) was clinically described in 1970, but it became mutated gene from a common ancestor and are thus identical recognised as a separate clinical entity in 1972.45CRMO is an by descent (homozygous) not only at the trait locus but also autoinflammatory disorder, that is, it is characterised by at neighbouring marker loci. seemingly unprovoked inflammation in the absence of The syndrome of CRMO and congenital dyserythropoietic autoimmunity or infectious causes. It is frequently associated anaemia (CDA), or Majeed syndrome, is a rare autosomal with a cutaneous inflammatory condition such as pustulosis recessive disorder first described in 1989.23 It is composed of palmoplantaris (PPP),6–8 Sweet syndrome,9–11 and psoriasis.12–14 three prominent features: CRMO, CDA, and an inflammatory Although CRMO usually occurs sporadically, several obser- vations point to a genetic component to its aetiology. There Abbreviations: CDA, congenital dyserythropoietic anaemia; CRMO, are at least three reports of affected siblings with normal chronic recurrent multifocal osteomyelitis; PPP, pustulosis palmoplantaris www.jmedgenet.com 552 Ferguson, Chen, Tayeh, et al dermatosis.23–25 Majeed syndrome has been described only in www.ncbi.nlm.nih.gov; http://genome.ucsc.edu; http:// two families, although two reported sporadic cases have a www.ensembl.org). We prioritised the genes in the region similar phenotype.26 27 The CRMO starts in infancy and according to their likelihood for producing the phenotype of continues relentlessly leading to retarded growth or joint Majeed syndrome, as follows: TGIF, HEC (KNTC2), EMILIN2, contractures or both.23–25 The CDA is variable in severity and LPIN2, METTL4. The remaining six genes were tissue specific characterised by microcytosis, both peripherally and in the (muscle or neuronal tissue) or the predicted function could bone marrow, which is not typical of any of the well not be logically related to the phenotype. The genomic characterised and classified forms of CDA.23–25 The neutro- sequences of the candidate genes were obtained from the philic dermatosis, Sweet syndrome, is the common reported genome databases and the primer pairs were designed to skin inflammation.23 Our group has previously reported six amplify the exons and the splice sites of the genes using the individuals with Majeed syndrome from three sibships from Primer3 program (http://frodo.wi.mit.edu/cgi-bin/primer3/ two unrelated families.23–25 The gene responsible for this primer3_www.cgi). The PCR amplification products were complex syndrome was mapped to a 5.5 cM interval on the run on an agarose gel, and the bands containing the short arm of chromosome 18. We then identified that amplified products were recovered and extracted from the homozygous mutations in LPIN2 are responsible for Majeed agarose by column purification. The amplified products were syndrome. sequenced using an automated ABI sequencer with dye terminator chemistry. Sequencing was performed for an METHODS obligate carrier and an affected individual from family A, an Subjects affected individual from family B, and a normal unrelated We identified a family from Jordan with four affected control. Once a mutation was identified in family A, the same individuals. A detailed family history was obtained and a exon was sequenced in all family members to see if it four generation pedigree was constructed (fig 1). The family segregated with both the phenotype and haplotype. We then members who agreed to participate in this study are four screened the control populations by both SSCP analysis and affected individuals and seven of their relatives (family A). A sequencing of suspicious bands. For family B, we sequenced second family with two affected individuals in one sibship the exon that carried the mutation in the other affected and first cousin parents was identified, but only the affected individual and developed an SSCP assay to screen the control individuals participated in the study (family B). Informed populations for that mutation. The sequences of the primers consent, approved by a local (Jordanian) institutional review used for the amplification of the exons and for the SSCP board, was provided by the participants or their legal analysis are included in the supplementary material which is guardian. We obtained 1064 controls from the HGDP-CEPH available at http://jmedgenet.com/supplemental. Human Genome Diversity Cell Line Panel,28 an additional 86 unrelated CEPH controls, and 367 anonymous Jordanian Structure of LPIN2 and its transcript control DNA samples. The structure of LPIN2 was obtained from the public genomic databases (D87436; NM_014646). Five human overlapping Genotyping cDNA clones covering the entire cDNA of LPIN2 were DNA was extracted
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