Mutations in STIL, Encoding a Pericentriolar and Centrosomal Protein, Cause Primary Microcephaly

Primary microcephaly (MCPH) is an autosomal-recessive congenital disorder characterized by smaller-than-normal brain size and mental retardation. MCPH is genetically heterogeneous with six known loci: MCPH1-MCPH6. We report mapping of a novel locus, MCPH7, to chromosome 1p32.3-p33 between markers D1S2797 and D1S417, corresponding to a physical distance of 8.39 Mb. Heterogeneity analysis of 24 families previously excluded from linkage to the six known MCPH loci suggested linkage of five families (20.83%) to the MCPH7 locus. In addition, four families were excluded from linkage to the MCPH7 locus as well as all of the six previously known loci, whereas the remaining 15 families could not be conclusively excluded or included. The combined maximum two-point LOD score for the linked families was 5.96 at marker D1S386 at theta = 0.0. The combined multipoint LOD score was 6.97 between markers D1S2797 and D1S417. Previously, mutations in four genes, MCPH1, CDK5RAP2, ASPM, and CENPJ, that code for centrosomal proteins have been shown to cause this disorder. Three different homozygous mutations in STIL, which codes for a pericentriolar and centrosomal protein, were identified in patients from three of the five families linked to the MCPH7 locus; all are predicted to truncate the STIL protein. Further, another recently ascertained family was homozygous for the same mutation as one of the original families. There was no evidence for a common haplotype. These results suggest that the centrosome and its associated structures are important in the control of neurogenesis in the developing human brain.

The Eligibility Definition Used in the Social Security Administration’s Disability Programs Needs to be Changed

In its October 2003 report on the definition of disability used by the Social Security Administration’s (SSA’s) disability programs [i.e., Social Security Disability Insurance (SSDI) and Supplemental Security Income (SSI) for people with disabilities], the Social Security Advisory Board raises the issue of whether this definition is at odds with the concept of disability embodied in the Americans with Disabilities Act (ADA) and, more importantly, with the aspirations of people with disabilities to be full participants in mainstream social activities and lead fulfilling, productive lives. The Board declares that “the Nation must face up to the contradictions created by the existing definition of disability.” I wholeheartedly agree. Further, I have concluded that we have to make fundamental, conceptual changes to both how we define eligibility for economic security benefits, and how we provide those benefits, if we are ever to fulfill the promise of the ADA. To convince you of that proposition, I will begin by relating a number of facts that paint a very bleak picture – a picture of deterioration in the economic security of the population that the disability programs are intended to serve; a picture of programs that purport to provide economic security, but are themselves financially insecure and subject to cycles of expansion and cuts that undermine their purpose; a picture of programs that are facing their biggest expenditure crisis ever; and a picture of an eligibility determination process that is inefficient and inequitable -- one that rations benefits by imposing high application costs on applicants in an arbitrary fashion. I will then argue that the fundamental reason for this bleak picture is the conceptual definition of eligibility that these programs use – one rooted in a disability paradigm that social scientists, people with disabilities, and, to a substantial extent, the public have rejected as being flawed, most emphatically through the passage of the ADA. Current law requires eligibility rules to be based on the premise that disability is medically determinable. That’s wrong because, as the ADA recognizes, a person’s environment matters. I will further argue that programs relying on this eligibility definition must inevitably: reward people if they do not try to help themselves, but not if they do; push the people they serve out of society’s mainstream, fostering a culture of isolation and dependency; relegate many to a lifetime of poverty; and undermine their promise of economic security because of the periodic “reforms” that are necessary to maintain taxpayer support. I conclude by pointing out that to change the conceptual definition for program eligibility, we also must change our whole approach to providing for the economic security of people with disabilities. We need to replace our current “caretaker” approach with one that emphasizes helping people with disabilities help themselves. I will briefly describe features that such a program might require, and point out the most significant challenges we would face in making the transition.

State Estimates of Employment Rates for Persons with Disabilities: Report Summary

Statistics on the states’ employment rates for persons with disabilities relative to their non-disabled peers may be of assistance to providers of employment services for persons with disabilities. Such information can help service providers, policy makers, and disability advocacy leaders to assess whether the employment rate of people with disabilities is improving over time, given policy, regulatory, and service intervention strategies. A recent report from the Cornell University Rehabilitation Research and Training Center (RRTC) for Economic Research on Employment Policy for Persons with Disabilities uses data from the March Current Population Survey to estimate employment rates for persons with and without a disability in the non-institutionalized working-age (aged 25 through 61) civilian population in the United States, and for each state and the District of Columbia for the years 1980 through 1998. The employment rate of persons with a disability relative to that of persons without disabilities are found to vary greatly across states. Over the last 20 years the relative employment rate of those with a disability dramatically declined overall and in most states.

Policy and Practice Brief: Representative Payment

This brief provides an overview of the Representative Payee program administered by Social Security. Discussed are the many provisions of the programs as well as practice tips and implications for BPA&O and PABSS personnel.

Universal Access-NY User’s Guide

What is Universal Access-NY? Universal Access-NY is a complete online planning toolkit, www.UniversalAccessNY.org, where a One-Stop Delivery System can assess its practices, and develop work plans to improve physical and programmatic accessibility for all One-Stop customers. This web site and manual was developed by Cornell University’s Employment and Disability Institute, through the support and guidance of the New York State Department of Labor, with funding from two U.S. Department of Labor Work Incentive Grants (WIG 1 and 2). This web site was designed for use in a collaborative manner, bringing together One-Stop personnel, agency partners, business leaders and customers with disabilities. Universal Access-NY supports continuous improvement, with features that encourage multiple uses and incremental systems change.

Discovering an Untapped Resource: Recruiting, Hiring, and Promoting People with Cognitive Disabilities.

Sections to the Paper include the following: America's Shrinking Labor Force, People with Cognitive Disabilities: an Untapped Labor Source, Focus, Initiative, Understand, Enhance.

When are SSDI/SSI Benefits Paid Pending Appeal?

This Just the Facts Series details when SSDI/SSI benefits are paid pending appeal.

A Comparison of the Implementation of the Employment Provisions of the Americans with Disabilities Act of 1990 (ADA) in the United States and the Disability Discrimination Act (DDA) 1995 in the United Kingdom

This summarizes the results of recently conducted surveys in the United States and Britain to assess employer response in each of these countries to their respective employment disability nondiscrimination legislation.

Promising Practices: Ensuring Choice Under the Ticket to Work Program - The Indiana PABSS Approach

The Ticket to Work program offered disabled and blind social security beneficiaries the promise of greater choice when selecting a vocational rehabilitation provider. With the issuance of Transmittal #17, much of the opportunity to choose a provider was removed. The Protection and Advocacy agency in Indiana took steps to protect the rights of disabled and blind beneficiaries to choose providers in the face of this significant policy change. Learn what was done to protect the rights and ability of beneficiaries to seek and choose vocational rehabilitation providers.

The Benefits Planner: Improved Work Incentives in Social Security Disability Insurance Program - Changes Will Make Work More Attractive to SSDI Recipients

This newsletter will provide valuable information on how work for persons with disabilities effects government benefits, with an emphasis on the Supplemental Security Income (SSI) and Social Security Disability Insurance (SSDI) work incentives. Each newsletter will contribute to an ongoing dialogue on topics related to benefits and work.

The Benefits Planner: New York Implements Medicaid Buy-In Program - Program Allows Individuals With Disabilities to Work and Keep Medicaid

This newsletter will provide valuable information on how work for persons with disabilities effects government benefits, with an emphasis on the Supplemental Security Income (SSI) and Social Security Disability Insurance (SSDI) work incentives. Each newsletter will contribute to an ongoing dialogue on topics related to benefits and work.

Developing Strategic Marketing Plan

This publication is first in a series targeted for Coordinators and Managers within Benefits Planning, Assistance and Outreach Programs concerned with developing continuous quality improvement approaches. This early publication focuses on understanding strategies for market position, strategic planning and provides a tool for conducting an organizational self-assessment along with a stakeholder analysis

A Guide to Disability Statistics from the National Health Interview Survey – Disability Supplement

The National Health Interview Survey - Disability supplement (NHIS-D) provides information that can be used to understand myriad topics related to health and disability. The survey provides comprehensive information on multiple disability conceptualizations that can be identified using information about health conditions (both physical and mental), activity limitations, and service receipt (e.g. SSI, SSDI, Vocational Rehabilitation). This provides flexibility for researchers in defining populations of interest. This paper provides a description of the data available in the NHIS-D and information on how the data can be used to better understand the lives of people with disabilities.

Disability in a Technology-Driven Workplace

New Internet and Web-based technology applications have meant significant cost and time efficiencies to many American businesses. However, many employers have not yet fully grasped the impact of these new information and communication technologies on applicants and employees with certain disabilities such as vision impairments, hearing problems or limited dexterity. Although not all applicants and employees who have a disability may experience IT-access problems, to select groups it can pose a needless barrier. The increasing dominance of IT in the workplace presents both a challenge and an opportunity for workers with disabilities and their employers. It will be up to HR professionals to ensure that Web-based HR processes and workplace technologies are accessible to their employees with disabilities. .

The molecular basis of Marinesco-Sjögren syndrome

Marinesco-Sjögren syndrome (MSS) is a rare autosomal recessive neurodegenerative disorder characterized by cerebellar ataxia due to cerebellar cortical atrophy, infantile- or childhood-onset bilateral cataracts, progressive myopathy, and mild to severe mental retardation. Additional features include hypergonadotropic hypogonadism, various skeletal abnormalities, short stature, and strabismus. The neuroradiologic hallmarks are hypoplasia of both the vermis and cerebellar hemispheres. The histopathologic findings include severe cerebellar atrophy and loss of Purkinje and granule cells. The common pathologic findings in muscle biopsy are variation in muscle fiber size, atrophic fibers, fatty replacement, and rimmed vacuole formation. The presence of marked cerebellar atrophy with myopathy distinguishes MSS from another rare syndrome, the congenital cataracts, facial dysmorphism, and neuropathy syndrome (CCFDN). Previously, work by others had resulted in the identification of an MSS locus on chromosome 5q31. A subtype of MSS with myoglobinuria and neuropathy had been linked to the CCFDN locus on chromosome 18qter, at which mutations in the CTDP1 gene had been identified. We confirmed linkage to the previously identified locus on chromosome 5q31 in two Finnish families with eight affected individuals, reduced the critical region by fine-mapping, and identified SIL1 as a gene underlying MSS. We found a common homozygous founder mutation in all Finnish patients. The same mutation was also present in patient samples from Norway and Sweden. Altogether, we identified eight mutations in SIL1, including nonsense, frameshift, splice site alterations, and one missense mutation. SIL1 encodes a nucleotide exchange factor for the endoplasmic reticulum (ER) resident heat-shock protein 70 chaperone GRP78. GRP78 functions in protein synthesis and quality control of the newly synthesized polypeptides. It senses and responds to stressful cellular conditions. We showed that in mice, SIL1 and GRP78 show highly similar spatial and temporal tissue expression in developing and mature brain, eye, and muscle. Studying endogenous proteins in mouse primary hippocampal neurons, we found that SIL1 and GRP78 colocalize and that SIL1 localizes to the ER. We studied the subcellular localization of two mutant proteins, a missense mutant found in two patients and an artificial mutant lacking the ER retrieval signal, and found that both mutant proteins formed aggregates within the ER. Well in line with our findings and the clinical features of MSS, recent work by Zhao et al. showed that a truncation of SIL1 causes ataxia and cerebellar Purkinje cell loss in the naturally occurring woozy mutant mouse. Prior to Purkinje cell degeneration, the unfolded protein response is initiated and abnormal protein accumulations are present. MSS thus joins the group of protein misfolding and accumulation diseases. These findings highlight the importance of SIL1 and the role of the ER in neuronal function and survival. The results presented in this thesis provide tools for the molecular genetic diagnostics of MSS and give a basis for future studies on the molecular pathogenesis of MSS. Understanding the mechanisms behind this pleiotropic syndrome may provide insights into more common forms of ataxia, myopathy, and neurodegeneration.