natural selection solidifies the most favorable alterations in our replicative processes to create brilliantly functional biochemical and cellular pathways .
hence , it is axiomatic that rare diseases , in addition to being coruscating curiosities , also serve as windows to the world s normal order . among the women and men who address human mutations , clinicians provide care for those affected with rare maladies , and a special cadre of scientists investigates the causes of those disorders .
the nih undiagnosed diseases program ( udp ) , announced may 19 , 2008 , serves as a focal point for the synergistic interplay between clinical and basic science investigators ( gahl and tifft , 2011 ; gahl et al . , 2011 ) .
the udp filters thousands of enquiries down to hundreds of nih clinical center inpatient admissions , and then chooses illustrative cases to pursue experimentally .
three years into its operation , the udp had reviewed more than 1800 thick medical records , accepted approximately 430 patients and admitted 350 of them .
the program had performed close to 600 single nucleotide polymorphism ( snp ) arrays and analyzed approximately 230 whole exome sequences ( wess ) using dna from patients and their family members .
many specific cases warranted intense investigation , based on their compelling clinical presentations , the likelihood that the basic defects would be uncovered and the impact predicted to emanate from the  new disease discovery. in the sections below , we recount examples that illustrate the process of disease discovery and how it can , in turn , provide new information about the role of genes and biological pathways in normal and impaired physiology .
for example , udp clinical investigators ascertained a family of five adults from middle america with stunning arterial calcification and claudication confined to the lower extremities ( st . hilaire et al . , 2011 ) .
intense clinical examinations verified that this was not atherosclerosis , that the coronaries were spared , and that the only additional sites of ectopic calcification involved the joint capsules of the hands and feet .
the next step involved applying genetic methodologies to identify candidate genes causing this disease . in this case , the project benefited enormously from the fact that the parents of the five siblings were third cousins , unaffected , and readily available for study . the most appropriate genetic platform to employ was the million snp array , which detects copy number variants ( deletions and duplications ) and also identifies regions of homozygosity . in a product of a consanguineous mating ,
most homozygous areas derive from a common ancestor , and a single pathogenic mutation in a shared ancestral gene could cause a recessive disease .
hence , we were looking for a region of the human genome in which all five affected siblings were homozygous , but the parents were heterozygous .
that area contained 92 genes ; any one of them could have contained a homozygous mutation that caused the arterial calcifications .
this was the third , and most crucial , step in discovering a new human disease , i.e. identifying and connecting with a basic scientist whose lab possessed expertise in the field . in this case ,
hilaire of the national heart , lung and blood institute were authorities on vascular cell metabolism , and cell - based assays were extant in the boehm lab .
hilaire cultured an affected patient s fibroblasts and performed expression analysis of candidate genes in the inherited homozygous region .
only one gene , nt5e , which encodes the cd73 protein , was differentially expressed .
direct sequencing of nt5e identified null mutations that resulted in complete inactivation of cd73 protein in all affected siblings .
this newly identified vascular disease was referred to as  arterial calcification due to deficiency of cd73 ( acdc ) .
cd73 is a membrane - bound enzyme that converts extracellular amp to adenosine and inorganic phosphate ; this process was found to be severely impaired in fibroblasts from individuals with acdc .
the failure to generate extracellular adenosine leads to an increase in tissue non - specific alkaline phosphatase ( tnap ) , a key enzyme in tissue calcification in vitro and in vivo .
cultured fibroblasts of individuals with acdc not only contained increased tnap activity , but they also calcified .
finally , tnap activity and in vitro calcification could be reversed by genetic rescue with nt5e cdna or treatment with exogenous adenosine .
the role of adenosine in inhibiting default calcification in vascular endothelial cells is a new concept that could have an enormous influence on our understanding of ectopic calcification in general .
the pathway might also have implications for other specific disorders , including monckeberg s medial sclerosis and pseudoxanthoma elasticum ( markello et al . , 2011 ) .
in addition , knowledge of the basic defect in acdc allows for consideration of treatment for affected individuals ; besides the five siblings described above , four other acdc patients have been ascertained worldwide , and still more have come to our attention recently .
treatment with bisphosphonates ( inhibitors of alkaline phosphatase ) is a potential therapy ; therefore , we have initiated a clinical protocol to test this .
a second example of disease discovery emanating from the nih udp focused on a novel spastic ataxia - neuropathy syndrome in two brothers ( pierson et al . , 2011 ) .
phenotyping revealed spasticity , peripheral neuropathy , cerebellar ataxia , oculomotor apraxia , dystonia and myoclonic epilepsy .
one of the brothers died at age 13 ; the other was deteriorating at age 14 .
again , consanguinity was involved , but this time in the form of a first cousin marriage .
whereas third cousins share 1/128 of their genes , first cousins share 1/8 of their genes , meaning that more than 10% of the human genome would be homozygous on snp array analysis . as a consequence
, snp arrays would yield too many candidate genes to guess which ones would warrant further pursuit .
wes involves massively parallel sequencing of 40 million bases that constitute the < 2% of the human genome ( 3.2 billion bases ) encoding genes .
using a whole exome platform , not every gene is perfectly sequenced ( i.e.  covered ) , but the breadth is so great that there is a good chance of detecting a causative variant .
the problem is that non - pathogenic variants abound , so the exome sequences of other family members are required to reduce ( 
filter ) the total number of variants . in the case of the two brothers , a total of 120,469 variants
were identified among the two parents and two affected brothers ; this was reduced to 59,482 variants not found in the 1000 genomes database . of these ,
11 were homozygous and , of the 11 , three were not present in dbsnp , a database of known polymorphisms .
one homozygous missense mutation ( c.1847g > a ; p.y616c ) in the afg3l2 gene was identified as the best candidate .
afg3l2 encodes a subunit of a mitochondrial aaa protease that removes damaged or misfolded proteins ( koppen et al . , 2007 ) . as in the case of acdc
, we had a phenotype and a gene , but needed scientific expertise to demonstrate a functional deficit and a mechanism of disease . in this case
, thomas langer and elena rugarli of the university of cologne in germany provided the basic research knowledge by using a yeast expression system to study afg3l2 .
it was known that afg3l2 protein forms either a homo - oligomeric isoenzyme or a hetero - oligomeric complex with paraplegin .
group used yeast complementation assays to show that the mutant ( y616c ) afg3l2 protein is a hypomorphic variant with an impaired ability to form complexes with either itself or with paraplegin ( pierson et al .
this finding was well aligned with the clinical phenotype , because paraplegin was mutated in hereditary spastic paraplegia type 7 ( spg7 ) , and heterozygous afg3l2 mutations caused autosomal dominant spinocerebellar ataxia type 28 ( sca28 ) ( atorino et al . , 2003 ; koppen et al . , 2007 ) .
the specific homozygous y616c mutation in our patients produced a unique combination of the phenotypes of spg7 and sca28 , along with other mitochondrial disease features such as oculomotor apraxia , extrapyramidal dysfunction and myoclonic epilepsy .
this new disease discovery significantly broadened the phenotypes associated with both spinocerebellar ataxia and hereditary spastic paraplegia for the neurological community .
the above examples employed a wide range of research modalities  including cutting - edge medical procedures , state - of - the - art genetics , appropriate cell culture systems and model organisms  to come to a final diagnosis .
the nih udp has many other cases similar to those mentioned above , at different stages of maturation , as well as examples of extremely rare , known diseases .
. , 2000 ) being investigated by immunologists , follicular hyperkeratosis being pursued by cell cycle experts and an autosomal dominant myopathy being studied by cell biologists . in every case ,
genetics ties the clinical investigator to the basic scientist , but some investigations lie fallow for want of bench researchers or experts in the disease . as our knowledge and data in genetics burgeon
, we must engage the cognoscenti in a wide variety of fields to discover new diseases , new mechanisms of action and , ultimately , new therapeutic interventions .
only a union of clinical and basic researchers  and an awareness of the rich resource that lies in the population of rare disease patients  can achieve this .
we hope that the udp can serve as a model for similar programs at major medical centers throughout the world .
 summarythe majority of the biomedical research workforce and funds are focused on studying common diseases and the development of drugs to treat them . 
 however , some of the most remarkable discoveries in physiology and medicine are uncovered by studying rare conditions , because the importance of certain molecular mechanisms is revealed only when their dysfunction results in disease . in 2008 , 
 the national institutes of health ( nih ) launched the nih undiagnosed diseases program ( udp ) , which recruits and selects patients who suffer from diseases of unknown etiology , and studies their causes at the clinical , genetic and cellular levels . in this editorial 
 , we discuss how the udp has enabled the discovery of several new diseases and disease mechanisms through collaborations between clinical and basic science teams , using the power of both clinical medicine and biological models . 
 establishing programs with similar infrastructure at other centers around the world could help to benefit patients , their families and the entire medical community , by enhancing research productivity for rare and novel diseases . 