Ferguson PJ, Chen S, Tayeh MK, Majeed HA, El-Shanti H. Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome)

Baylor College of Medicine, Houston, Texas, United States
Journal of Medical Genetics (Impact Factor: 6.34). 08/2005; 42(7):551-7. DOI: 10.1136/jmg.2005.030759
Source: PubMed


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.
Six individuals with Majeed syndrome from two unrelated families were identified for this study. Homozygosity mapping and parametric linkage analysis were employed for the localisation of the gene 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 identified causal gene and its protein were carried out.
The phenotype of Majeed syndrome includes inflammation of the bone and skin, recurrent fevers, and dyserythropoietic anaemia. The clinical picture of the six affected individuals is briefly reviewed. The gene was mapped to a 5.5 cM interval (1.8 Mb) on chromosome 18p. Examination of genes in this 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 inflammation remains unknown.
We conclude that homozygous mutations in LPIN2 result in Majeed syndrome. Understanding the aberrant immune response in this condition will shed light on the aetiology of other inflammatory disorders of multifactorial aetiology including isolated chronic recurrent multifocal osteomyelitis, Sweet syndrome, and psoriasis.

Download full-text


Available from: Hatem I El-Shanti
  • Source
    • "None of the other genes within the microdeletion have been reported to be sensitive to hemizygosity. Homozygous mutations in lipin 2 (LPIN2) have been associated with Majeed syndrome, characterized by chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia [Ferguson et al., 2005]. METTL4 (methyltransferase-like 4) encodes for a putative methyltransferase of unknown function, whereas NDC80 encodes a central component of the kinetochore protein complex necessary for proper chromosome segregation and spindle checkpoint signaling [Martin- Lluesma et al., 2002]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Facioscapulohumeral muscular dystrophy (FSHD) is most often associated with variegated expression in somatic cells of the normally repressed DUX4 gene within the D4Z4 repeat array. The most common form, FSHD1, is caused by a D4Z4 repeat array contraction to a size of 1-10 units (normal range 10-100 units). The less common form, FSHD2, is characterized by D4Z4 CpG hypomethylation and is most often caused by loss of function mutations in the structural maintenance of chromosomes hinge domain 1 (SMCHD1) gene on chromosome 18p. The chromatin modifier SMCHD1 is necessary to maintain a repressed D4Z4 chromatin state. Here we describe two FSHD2 families with a 1.2 Mb deletion encompassing the SMCHD1 gene. Numerical aberrations of chromosome 18 are relatively common and the majority of 18p deletion syndrome (18p-) cases have, like these FSHD2 families, only one copy of SMCHD1. Our finding therefore raises the possibility that 18p- cases are at risk of developing FSHD. To address this possibility, we combined genome wide array analysis data with D4Z4 CpG methylation and repeat array sizes in individuals with 18p- and conclude that approximately 1:8 18p- cases might be at risk of developing FSHD. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Full-text · Article · Mar 2015 · Human Mutation
  • Source
    • "Neutrophilic diseases share some clinical features with monogenic autoinflammatory disorders such as periodic fever and neutrophil infiltration in the skin and other organs. The SS was reported in monogenic disorders, such as Majeed syndrome [17]. But the differences in clinical manifestations, even within one group of ND, diversity in the subtypes of ND, and differences in the response to therapy [8] support the concept that neutrophilic diseases may be a new category named polygenic autoinflammatory diseases [1]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: A 7-year-old boy with high grade fever (39°C) and warm, erythematous, and indurated plaque above the left knee was referred. According to the previous records of this patient, these indurated plaques had been changed toward abscesses formation and then spontaneous drainage had occurred after about 6 to 7 days, and finally these lesions healed with scars. In multiple previous admissions, high grade fever, leukocytosis, and a noticeable increase in erythrocyte sedimentation rate and C-reactive protein were noted. After that, until 7th year of age, he had shoulder, gluteal, splenic, kidney, and left thigh lesions and pneumonia. The methylprednisolone pulse (30 mg/kg) was initiated with the diagnosis of Sweet’s syndrome. After about 10–14 days, almost all of the laboratory data regressed to nearly normal limits. After about 5 months, he was admitted again with tachypnea and high grade fever and leukocytosis. After infusion of one methylprednisolone pulse, the fever and tachypnea resolved rapidly in about 24 hours. In this admission, colchicine (1 mg/kg) was added to the oral prednisolone after discharge. In the periodic fever and neutrophilic dermatosis, the rheumatologist should search for sterile abscesses in other organs.
    Full-text · Article · Dec 2014 · Clinical Medicine: Case Reports
  • Source
    • "Suppression of inflammation may eventually prove to have therapeutic potential, but this is speculative. Mutations in LPIN2 cause Majeed syndrome (Ferguson et al 2005), an inflammatory condition reviewed elsewhere in this issue. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Triglyceride (TG) synthesis, storage, and degradation together constitute cytoplasmic TG metabolism (CTGM). CTGM is mostly studied in adipocytes, where starting from glycerol-3-phosphate and fatty acyl (FA)-coenzyme A (CoA), TGs are synthesized then stored in cytoplasmic lipid droplets. TG hydrolysis proceeds sequentially, producing FAs and glycerol. Several reactions of CTGM can be catalyzed by more than one enzyme, creating great potential for complex tissue-specific physiology. In adipose tissue, CTGM provides FA as a systemic energy source during fasting and is related to obesity. Inborn errors and mouse models have demonstrated the importance of CTGM for non-adipose tissues, including skeletal muscle, myocardium and liver, because steatosis and dysfunction can occur. We discuss known inborn errors of CTGM, including deficiencies of: AGPAT2 (a form of generalized lipodystrophy), LPIN1 (childhood rhabdomyolysis), LPIN2 (an inflammatory condition, Majeed syndrome, described elsewhere in this issue), DGAT1 (protein loosing enteropathy), perilipin 1 (partial lipodystrophy), CGI-58 (gene ABHD5, neutral lipid storage disease (NLSD) with ichthyosis and "Jordan's anomaly" of vacuolated polymorphonuclear leukocytes), adipose triglyceride lipase (ATGL, gene PNPLA2, NLSD with myopathy, cardiomyopathy and Jordan's anomaly), hormone-sensitive lipase (HSL, gene LIPE, hypertriglyceridemia, and insulin resistance). Two inborn errors of glycerol metabolism are known: glycerol kinase (GK, causing pseudohypertriglyceridemia) and glycerol-3-phosphate dehydrogenase (GPD1, childhood hepatic steatosis). Mouse models often resemble human phenotypes but may diverge markedly. Inborn errors have been described for less than one-third of CTGM enzymes, and new phenotypes may yet be identified.
    Full-text · Article · Oct 2014 · Journal of Inherited Metabolic Disease
Show more