Table of Contents  

Al-Aqeel: Al-Aqeel Sewairi syndrome, MIM#605156, a prototype for personalized medicine for the study and prevention of genetic metabolic disorders in Saudi Arabia

Introduction

Middle Eastern cultures are tribal and heavily consanguineous. Marriage between cousins has been part of the culture for millennia, leading to ‘founder’ effects and a large number of autosomal recessive diseases. In Saudi Arabia, as in other Middle East countries, first-cousin marriages account for almost 60–70% of all marriages, leading to disorders unique to the area which are either rare by Western standards or completely unknown.13 Most of these disorders lead to physical and mental handicap; affected children have poor development and reduced mental capacity. A review of our files over a 15-year period documented more than 150 varieties of neurodegenerative disease with mental subnormality among 2000 children; 27 of these diseases account for more than half of these cases. Some autosomal recessive disorders are unique, for example Al-Aqeel Sewairi syndrome. These diseases are clinically recognizable through certain symptoms and signs. Their early recognition is important to initiate treatment and to prevent neurological and mental crippling. The treatment of storage diseases, for example Gaucher's disease, Niemann–Pick type B disease and Morquio's disease, is experimental, through either administration of purified enzymes [Ceredase® (Genzyme, Cambridge MA, USA) for Gaucher's disease] or bone marrow transplantation. However, these treatment modalities are either difficult and expensive or unavailable in most centres.1 Therefore, prevention is important, either by newborn screening, premarital genetic screening, preimplantation genetic diagnosis or prenatal diagnosis, according to the ethical and religious recommendation of our Islamic scholars.2,3

Personalized genomics has been one of the long anticipated promises of the human genome project. Now that we have high-density single nucleotide polymorphism (SNP) genomic information available at affordable prices for clinical applications, and with the US $1000 next-generation genome sequencing not far away, we are encountering challenges to the implementation of personalized medicine for the best of our patients.

An example of the application of personalized genomics research in Saudi Arabia is the previously described novel autosomal recessive osteolysis or arthritis syndrome, multicentric osteolysis nodulosis with arthritis (MONA) (NOA) (Al-Aqeel Sewairi syndrome; MIM#605156), a distinctive autosomal recessive multicentric osteolysis in Saudi Arabian families with distal arthropathy of the metacarpal, metatarsal and interphalangeal joints, and ultimate progression to the proximal joints leading to decreased range of movement, deformities with ankylosis and generalized osteopenia. In addition, patients have large, painful palmar and plantar pads, hirsutism and mild dysmorphic facial features including proptosis, a narrow nasal bridge, bulbous nose and micrognathia.4,5

The Al-Aqeel-Sewairi syndrome is caused by inactivating mutations of the matrix metalloproteinase 2 (MMP2) gene.69

Results

We used a genome-wide search for microsatellite markers from six members of the index family, and we succeeded in localizing the gene to chromosome 16q12–21 with a LOD [logarithm (base 10) of odds] score of 4.59. Haplotype analysis with additional markers narrowed the critical region to 1.2 cM between markers D16S3032 and D16S3140, and identified the MMP2 (gelatinase A, collagenase type IV,EC 3.4.24.24) gene as a disease candidate. All affected individuals were then found to be homoallelic for a nonsense mutation (TCA>TAA) in codon 244 of exon 5, predicting the replacement of a tyrosine residue by a stop codon in the first fibronectin type II domain (Y244X). In a second family we found a G→A transition in codon 10 of exon 2, predicting the replacement of an arginine with histidine (R101H). In a third family, no inactivating mutations were found in the exonic sequences of the gene; such mutation might be present in the promoter or intrinsic sequences. However, a non-pathogenic homoallelic G→T polymorphism resulted in the replacement of an aspartate with a tyrosine residue (D210Y), which was also present in 50 unaffected members of the tribe; all affected members had no serum and fibroblastic MMP2 enzyme activity, whereas parents, heterozygote siblings, had half-normal levels of MMP2 activity.69

The discovery that deficiency of this well characterized gelatinase/collagenase results in an inherited form of an osteolytic and arthritic disorder provides invaluable insights for the understanding of osteolysis and arthritis and the in vivo function of MMP2.69

We report that Mmp2–/– mice display attenuated features of human MONA including progressive loss of bone mineral density, articular cartilage destruction and abnormal long bone and craniofacial development. Moreover, these changes are associated with markedly and developmentally restricted decreases in osteoblast and osteoclast numbers in vivo. Mmp2–/– mice have 50% fewer osteoblasts and osteoclasts than control littermates at 5 days of life.10

Targeted inhibition of MMP2 using single standard RNA (siRNA) in human SaOS2 and murine MC3T3 osteoblast cell lines resulted in decreased cell proliferation rates. Taken together, our findings suggest that MMP2 plays a direct role in early skeletal development and bone cell growth and proliferation. Thus, Mmp2–/– mice provide a valuable biological resource for studying the pathophysiological mechanisms underlying the human disease and defining the in vivo physiological role of MMP2. This mouse model provided us with insight for targeted gene discovery for the treatment of this disorder10 and for stem cell therapy.11

Discussion

The matrix metalloproteinases (MMPs), also called matrixins, are a family of zinc- and calcium- dependent and membrane-associated endopeptidases that are active at neutral pH. Each member has specificity for a subset of extracellular matrix (ECM) molecules; collectively they catalyse the proteolysis of all components of the ECM,12 as well as other extracellular non-matrix proteins.13 The expression of most matrixins is transcriptionally regulated by growth factors, hormones, cytokines and cellular transformation.14

The development of a multicellular organism is dependent on an ECM, which facilitates the organization of cells into more complex functional units: tissues and organs. The ECM is the glue that holds cells together, and provides texture, strength and integrity to the tissues. Diversity in tissue function depends not only on diversity in cell types but also upon diversity in the composition of the ECM. Bone, for example, comprises one type of ECM; that of lung and brain is quite different. It has become increasingly apparent that the ECM harbours informational cues that direct cell behaviour. In fact, the interaction of a cell with its ECM regulates some of the most fundamental cellular processes, such as growth, survival, differentiation, motility, signal transduction and changing shape.8,9,12,15

Matrix metalloproteinases participate in many normal biological processes (e.g. embryonic development, blastocyst implantation, organ morphogenesis, nerve growth, ovulation, cervical dilatation, post-partum uterine involution, endometrial cycling, hair follicle cycling, bone remodelling, wound healing, angiogenesis and apoptosis)13,1618 and pathological processes (e.g. arthritis, cancer, cardiovascular disease, nephritis, neurological disease, breakdown of blood–brain barrier, periodontal disease, skin ulceration, gastric ulcer, corneal ulceration, and fibrosis of the liver and lung).13,1520

Matrix metalloproteinases are regulated at different levels. These MMPs are synthesized as pre–proenzymes and secreted as active pro-MMPs in most cases,21,22 which are activated by membrane-type MMPs (MT-MMPs). However, inhibition of MMPs is by endogenous tissue inhibitors (tissue inhibitors of metalloproteinases; TIMPS). Currently, four of them are known. MT1-MMP is a membrane-associated MMP that is highly expressed in osteocartilagenous and musculotendinous structures23,24 and may function as a pericellular activator of MMP2 in a trimeric complex with TIMP2 and MMP2.8,9,2227

Matrix metalloproteinase 2 is thought to regulate the activity of a critical growth factor, transforming growth factor β (TGF-β). TGF-β signalling mediates the coupling of the reciprocal activities of bone formation and resorption by influencing the maturation of osteocytes and enhancing the activity of osteoclasts.8,9,12,25 Physiologically, TGF-β may co-ordinate osteoclast activity by recruiting osteoclasts to existing sites of resorption. Pathologically, TGF-β-induced osteoclast recruitment may be critical for expansion of primary and metastatic tumours in bone.26,27 Plasmin, elastase, MMP9 and MMP2 activate TGF-β by proteolytically cleaving the latent associated peptide, i.e. latent TGF-β-binding protein (LTBp1) to produce 125- to165-kDa fragment which is the physiological mechanism for the release of active TGF-β from ECM-bound stores.2729 Lack of MMP2 may therefore affect bone formation and homeostasis through modulating the level of active TGF-β.8,9

The ECM remodelling is important for morphogenesis and homeostasis. The balancing act of ECM deposition and breakdown is very critical; therefore, MMP2 deficiency leads to an imbalance between the breakdown and deposition of the ECM.8,9,12 Tissue fibrosis may be attributed to impaired function of fibroblasts, arthritis and osteolysis to increased osteoclastic activity, and craniofacial dysmorphism and osteopenia to impaired function of osteoblasts.810,12 MONA represents the unique intersection of a rare genetic disease and an a priori candidate gene, albeit by a completely counterintuitive mechanism.8,9,12,30,31 On the basis of their substrate specificity and biological plausibility, MMPs would be expected to play an important role in skeletogenesis, and as our initial genetic studies, evidence now exists for three other MMPs, MMP9, MMP13 and MT1-MMP, in bone development.10 Taken together, our current results demonstrate that MMP2 deficiency results in a unique bone phenotype in mice comparable in many respects with that seen in the human disease and that, in part, this results from a previously unappreciated role for MMP2 activity on osteoblast and osteoclast behaviour and development.810 In addition to the Al-Aqeel Sewairi syndrome, we also reported various unique variants of metabolic disorders including biopterin-dependent phenylketonuria , the Saudi variant of multiple sulphatase deficiency (Austin's disease), vitamin D-dependent rickets type II, carnitine acylcarnitine translocase deficiency, carnitine palmitoyl transferase type I deficiency, among others, and found their exact molecular defects.3249

Using genetics to benefit society requires that empirically verified knowledge be used within an ethical framework that combines appeal to written precedent with sensitivity to the options of individuals and families dealing with choices and necessities within the laws, norms and traditions of their society. Islamic bioethics is derived from a combination of principles, duties and rights and, to a certain extent, a call to virtue. It emphasizes prevention, and teaches that the patient must be treated with respect and compassion, and that the physical, mental and spiritual dimensions of the illness experience should be taken into account. These fundamental principles are important for implementing many preventative programmes and genomic research, in the presence of flexibility to respond to new biomedical technologies.2,3

For all these inherited disorders, we have established with other colleagues systematic prevention by preimplantation genetic diagnosis with success in over 160 cases in whom the result was the birth of normal children, including patients with Al-Aqeel Sewairi syndrome (Table 1).5058 We also established stem cell therapy for genetic metabolic disorders with a US$10 million grant, with Al-Aqeel Sewairi syndrome as the prototype for this promising modality for treatment of mental and physical handicap in children.11 These preventative and therapeutic strategies were done in accordance with our ethical and religious background, with priorities given to rights of patients and families to know and to decide for themselves as dictated by our Islamic ethics.2,3,5963

TABLE 1

Examples of some inherited diseases for which PGD was done54

Achondroplasia Maple syrup urine disease
Adrenoleucodystrophy Metachromatic leucodystrophy
Albinism, oculocutaneous type IA Microphthalmia/anophthalmia
α-Thalassaemia/mental retardation syndrome MONA syndrome
Argininosuccinic acidaemia Mucopolysaccharidosis, type I (Hurler syndrome)
Ataxia telangiectasia mutated Mucopolysaccharidosis, type II (Hunter syndrome)
Biotinidase deficiency Mucopolysaccharidosis, type IVA (Morquio's disease A)
Bosley–Salih–Alorainy syndrome Mucopolysaccharidosis, type VI (Maroteaux–Lamy syndrome)
β-Thalassaemia Niemann–Pick disease
Canavan's disease Non-ketotic hyperglycaemia
Carnitine acylcarnitine translocase deficiency Osteogenesis imperfecta type IV
Chronic granulomatous disease Phenylketonuria
Citrullinaemia Progressive familial intrahepatic cholestasis
Congenital adrenal hyperplasia Propionic acidaemia
Cystic fibrosis Sanfilippo syndrome type B (MPS-IIIB)
Duchenne muscular dystrophy Sanjad Sakati syndrome
Ehlers–Danlos syndrome Severe combined immunodeficiency disease
Fragile X Sickle cell disease
Galactosomia Smith–Lemli–Opitz syndrome
Glucose-6-phosphate dehydrogenase deficiency Spinal muscular atrophy/Werdnig–Hoffmann disease
Glutaric acidaemia type 1 Sulphite oxidase deficiency
Glycogen storage disease type II, Pompe's disease Tyrosinaemia type I
GM1 gangliosidosis Very long-chain acylCoA dehydrogenase deficiency
Hereditary non-syndromic sensorineural deafness Wiskott–Aldrich syndrome
Hyperinsulinaemia X-linked hydrocephalus
Joubert syndrome (JBTS3) Zellweger syndrome

Conclusion

In conclusion, personalized medicine for inherited metabolic disorders includes diagnostic and prognostic approaches, and must include personalized preventative and therapeutic strategies. We are also establishing stem cell therapy for genetic metabolic disorders with a grant of US$10 million.

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